HK1158703B

HK1158703B - Genetic markers for weight management and methods of use thereof

Info

Publication number: HK1158703B
Application number: HK11112954.6A
Authority: HK
Inventors: C‧达珀; L‧维尔金斯; G‧布里顿; L‧佩鲁瑟; R‧德巴斯克; S‧拉马克里施南; D‧克雷姆平
Original assignee: Orig3N, Inc.; 艾克赛斯商业集团国际有限责任公司
Priority date: 2008-05-16
Filing date: 2009-05-15
Publication date: 2016-07-15

Description

Genetic markers for weight management and methods of use thereof

Cross-reference to related applications:

this application claims priority from U.S. provisional patent application No. 61/053,888, filed on 16/5/2008, which is hereby incorporated by reference in its entirety.

Technical Field

The present application relates to methods of determining a subject's metabolic genotype and methods of selecting an appropriate therapeutic/dietary regimen or recommended lifestyle based on the subject's metabolic profile, and susceptibility to reverse weight management problems.

Background

According to the report published in 1998 by the World Health Organization (WHO), obesity reaches rampant proportions worldwide: approximately 17 hundred million people worldwide are overweight, and 3 hundred million of them are obese. In the united states, approximately one hundred two thousand seven million adults weigh too much and six thousand nine million of them are obese. Obese subjects have an increased risk of suffering from one or more serious medical conditions, including diabetes, heart disease, hypertension, and high blood cholesterol levels. The incidence of obesity has increased more than 2-fold over the past 25 years, and now 31% of adults aged 20 and older in the united states suffer from obesity. Obesity has a higher incidence (30% to 50%) in african americans and hispanic americans, especially women.

Over the past decade, the incidence of obesity has increased worldwide due to environmental changes, which refer to a gradual reduction in physical activity levels and the intake of abundant, highly palatable foods. The world health organization reports that these changes are two fundamental features of modern lifestyle that contribute to the development of obesity. However, not all people become obese despite exposure to the same environment, suggesting a role for the subject genetic profile in the development of weight management problems. That is, when exposed to adverse environments, genetic genes determine a subject's susceptibility to obesity and the subject's mode of response to daily diet and exercise.

Accordingly, there is a need for a method of establishing a personal weight loss program that takes into account the genetic susceptibility of an individual to obesity and provides improved weight loss and weight maintenance results relative to similar programs that do not take into account genetic information. At the same time, there is a need for a method of correlating the subject's metabolic genotype with response to diet and/or exercise.

The disadvantages and problems of the known methods described herein are not meant to limit the embodiments described herein beyond these disadvantages and problems.

Disclosure of Invention

The present invention provides methods and kits for determining a subject's metabolic genotype and selecting an appropriate therapeutic/dietary regimen or recommended lifestyle. According to some embodiments, provided herein are methods of determining the metabolic genotype of a subject, methods of classifying a subject into one or more nutritional and exercise categories to which the subject may be susceptible, and methods of communicating to the subject an appropriate treatment/diet regimen or recommended lifestyle. In this manner, an individual weight loss program can be selected based on the subject's metabolic genotype. Such personalized weight loss programs have significant advantages (e.g., produce better results in terms of weight loss and weight maintenance) over traditional weight loss programs that do not take into account genetic information.

According to some embodiments, there is provided a method of selecting an appropriate treatment/diet regimen or lifestyle recommendation for a subject, the method comprising: determining the genotype of the subject based on any two, any three or any four polymorphic sites selected from a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, a beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site or a B-2 adrenergic receptor (ADRB2) (rs 1042714; C/G) site; wherein the genotype of the subject determined from the locus provides information on the subject's increased sensitivity to reverse weight management problems and allows selection of a treatment/diet regimen or recommended lifestyle appropriate for the subject based on the subject's sensitivity to reverse weight management problems.

According to some embodiments, provided herein is a method of selecting an appropriate treatment/dietary regimen or recommended lifestyle for a subject, the method comprising: a) according to fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site or β -2adrenergic receptor (ADRB2) (rs 1042714; C/G) site, wherein the genotype of the subject determined from the site provides information on the subject's increased sensitivity to reverse weight management problems and allows for selection of a treatment/diet regimen or recommended lifestyle suitable for the subject based on the subject's sensitivity to reverse weight management problems.

According to some embodiments, there is provided a method of selecting an appropriate treatment/diet regimen or lifestyle recommendation for a subject, the method comprising: a) according to a protein selected from fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site or β -2adrenergic receptor (ADRB2) (rs 1042714; C/G) any two, any three or any four polymorphic sites in the sites determine the genotype of the subject; and b) classifying the subject genotype into a nutritional response type class and/or a motor response type class. Once a subject's genotype is classified or categorized as a nutritional response type category and/or a motor response type category, the subject may be provided with a treatment/diet regimen or recommended lifestyle, including, but not limited to, selecting an appropriate diet and activity level based on the type to which the subject is more likely to respond.

According to some embodiments, there is provided a method of selecting an appropriate treatment/diet regimen or lifestyle recommendation for a subject, the method comprising: a) according to a protein selected from fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site or β -2adrenergic receptor (ADRB2) (rs 1042714; C/G) any two, any three or any four polymorphic sites in the sites determine the genotype of the subject; and b) classifying the subject genotype into a nutritional response type class and/or a motor response type class.

According to some embodiments, there is provided a method of selecting an appropriate treatment/diet regimen or lifestyle recommendation for a subject, the method comprising: a) detecting an allelic profile selected from at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight alleles: fatty acid binding protein 2(FABP2) Single Nucleotide Polymorphism (SNP) rsl799883, allele 1 (genotype: G; amino acid: alanine); fatty acid binding protein 2(FABP2) Single Nucleotide Polymorphism (SNP) rsl799883, allele 2 (genotype: A; amino acid: threonine); peroxidase proliferation factor activated receptor-gamma (PPARG) Single Nucleotide Polymorphism (SNP) rsl801282, allele 1 (genotype: C; amino acid: proline); peroxidase proliferation factor activated receptor-gamma (PPARG) Single Nucleotide Polymorphism (SNP) rsl801282, allele 2 (genotype: G; amino acid: alanine); the Single Nucleotide Polymorphism (SNP) rs4994 of the beta-3 adrenergic receptor (ADRB3), allele 1 (genotype: T; amino acid: tryptophan); the Single Nucleotide Polymorphism (SNP) rs4994 of the beta-3 adrenergic receptor (ADRB3), allele 2 (genotype: C; amino acid: arginine); single Nucleotide Polymorphism (SNP) rsl042713 of beta-2adrenergic receptor (ADRB2), allele 1 (genotype: G; amino acid: glycine); single Nucleotide Polymorphism (SNP) rsl042713 of beta-2adrenergic receptor (ADRB2), allele 2 (genotype: A; amino acid: arginine); beta-2adrenergic receptor (ADRB2) Single Nucleotide Polymorphism (SNP) rsl042714, allele 1 (genotype: C; amino acid: glutamine); and a β -2adrenergic receptor (ADRB2) Single Nucleotide Polymorphism (SNP) rsl042714, allele 2 (genotype: G; amino acid: glutamic acid) site, wherein the presence of the allelic profile is predictive of the subject's response to daily diet and/or exercise, and (b) selecting a treatment/diet regime or recommended lifestyle that is compatible with the subject's predicted response to daily diet and/or exercise.

According to some embodiments, there is provided a method of identifying a metabolic genotype of a subject, the method comprising: the genotype of the subject is identified based on any two, any three or any four polymorphic sites selected from the group consisting of a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, a beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, there is provided a method of identifying a metabolic genotype of a subject, the method comprising: the genotype of the subject is identified based on the fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, the beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, the beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or the beta-2adrenergic receptor (ADRB2) (1042714; C/G) site.

According to some embodiments, there is provided a kit comprising means for genotyping a subject, wherein the subject is genotyped according to fatty acid binding protein 2(FABP2) (rsl 799883; G/a) site, peroxisome proliferator activated receptor- γ (PPARG) (rsl 801282; C/G) site, β -3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, β -2adrenergic receptor (ADRB2) (rsl 042713; a/G) site, and/or β -2adrenergic receptor (ADRB2) (rs 1042714; C/G) site. The kit further comprises sample collection means. The kit may also include both positive or negative control samples or a normalization means and/or a calculation means for evaluating results and other reagents and components.

The kit of the invention may be in the form of a DNA assay for providing recommended daily diet and exercise to a subject based on the genotype of the subject as recognized by the fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, the beta-3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, the beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or the beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site. The information provided by the subject's genotype may help health professionals study individual diet and exercise regimens, improving the prevention and treatment of obesity.

Other embodiments and advantages of the invention are set forth in the following detailed description and appended claims.

Detailed description of the preferred embodiments

The kits and methods of the invention rely, at least in part, on the discovery that there is some correlation between the manner in which certain metabolic alleles are present and the subject's response to certain dietary and exercise regimens. That is, there is a link between allelic patterns of metabolic genes and clinical outcomes and phenotypes associated with weight management. Certain genes can affect multiple pathways that act on body weight, and are associated with increased risk of developing obesity, and, due to differences in genotype, their ability to respond to differentiated subjects with weight management intervention. For the purpose of the present invention, such a gene is referred to as a "metabolic gene" or a "weight management gene". These genes include, but are not limited to, fatty acid binding protein 2(FABP 2); peroxidase proliferation factor activated receptor-gamma (PPARG); beta-2adrenergic receptors (ADRB2) and beta-3 adrenergic receptors (ADRB 3).

The present invention provides a weight management test to determine a subject's "metabolic genotype," which test comprises determining the genotype of one or more (e.g., 2, 3, 4, etc.) metabolic genes of the subject. The results of genotyping can be used to predict the response of a subject to relative macronutrient and calorie restriction in the daily diet for weight loss with or without exercise. Identifying the genotype of a subject can allow the subject to be matched to a treatment regimen, nutritional regimen, or lifestyle regimen, or a combination thereof, thereby devising a strategy to achieve and/or sustain weight loss. Thus, according to certain embodiments, polymorphic genotyping results (for a single polymorphism or a combination thereof) may be used to determine: 1) genetic impact/outcome to weight management interventional therapy, and 2) response to major nutrient and energy limitation in the daily diet for weight loss with or without exercise.

Collectively, determining the genotype of one or more metabolic genes in a subject can lead to a feasibility report for selecting an appropriate treatment/diet regimen or recommended lifestyle for the subject. A weight management test is designed which detects a subject's pattern of genetic polymorphisms based on one or more metabolic genes and uses such a weight management test to determine a subject's metabolic genotype. By identifying the corresponding genetic polymorphisms and genotype pattern outcomes, the test can assess the risk of possible weight management outcomes and direct subjects to select nutritional and lifestyle intervention therapies that match their individual genetic makeup.

Metabolism gene

Metabolic genes include, but are not limited to, fatty acid binding protein 2(FABP 2); peroxidase proliferation factor activated receptor-gamma (PPARG); beta-2adrenergic receptors (ADRB2) and beta-3 adrenergic receptors (ADRB 3). The subject displays the subject's metabolic genotype based on the pattern of genetic polymorphism of one or more of these genes. More preferably, the metabolic genotype of the subject is determined by identifying one or more (e.g., 2, 3, 4, or 5) genetic polymorphisms in the subject based on the fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, the peroxidase proliferation factor activated receptor- γ (PPARG) (rsl 801282; C/G) site, the β -3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, the β -2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or the β -2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

Fatty acid binding protein 2(FABP2) rsl799883 (Ala54 Thr; G/A) polymorphism.

The fatty acid binding protein 2(FABP2) gene encodes an intestinal form of fatty acid binding protein, a family of proteins that regulate lipid transport and metabolism. Fatty acid binding protein 2(FABP2) was found to be located in small intestinal epithelial cells where fatty acid binding protein 2(FABP2) controls fat absorption. In vitro, the Thr54 form of the protein shows more than 2-fold binding affinity for long-chain fatty acids (see Baier et aL, J Clin Invest 95: 1281-1287, 1995(Baier et aL, 1995 in the literature on "clinical investigation of impurities" at 1281-1287, 95)), and is associated with enhanced absorption of fat in the gut (see Levy et aL, J Biol Chem 276: 39679-39684, 2001(Levy et aL, 2001, at 39276-39679-39684, 2001)). Thus, the Thr54 variant is capable of increasing the absorption and/or processing of dietary fatty acids through the intestinal tract, and thereby increasing fat oxidation. Based on the recent obesity gene profile, a total of 5 studies demonstrated a link between the fatty acid binding protein 2(FABP2) gene and obesity; four of these involved the Ala54Thr polymorphism. The 54Thr variant is associated with increased BMI and body fat (Hegele et al, Clin Endocrinol Metab 81: 4334-) -4337, 1996(Hegele et al, 1996, Proc. Clin Endocrinology "81: 4334-) -4337), increased abdominal fat in Japanese men (Yamada et al, Diabetolonia 40: 706-) -710, 1997(Yamada et al, 1997, published on Glycomiasis" 40: 706-) -710), and higher leptin (leptin) levels in obesity and women (Albala et al, Obes Res 12: 340-) -345, 2004(Albala et al, 2004, published on "Observation study" 12: 340-)).

Numerous studies have shown that Ala54Thr polymorphism affects the response of subjects to detect dietary fat changes in food. Non-esterified fatty acids (NEFA) were 20% higher in the 54 Thr/threonine homozygote host than in the 54 Ala/alanine homozygote host after 7 hours of feeding at high fat meals (Pratley et al, J Lipid Res 41: 2002-. The 54Thr allele is also thought to be associated with increased levels of triglycerides after ingestion of fat (Agren et al, Arterioscler Thromb Val Biol 18: 1606-1610, 1998(Agren et al in 1998 at "Arterioscler Thromb Val Biol" p.18: 1606-1610)), with increased levels of 14-18 carbon chain fatty acids (Agren et al, Am J Clin Nutr 73: 31-35, 2001(Agren et al in 2001 at "clinical nutritional impurities" p.73: 31-35)). The postprandial Metabolism profile after eating the trans fatty acid-rich test diet relative to that after eating the cis fatty acid-rich diet showed that subjects with at least one copy of the Thr54allele exhibited increased postprandial glucose levels and adipogenesis compared to those homobound to the Ala54 allele (Lefevreet al, Metabolism 54: 1652-1658, 2005(Lefevre et al, published on "Metabolism" page 54 1652-1658 in 2005)). The lifestyle modification program consisted of a low calorie diet (1,520 kcal/day) and three aerobic exercises performed weekly (de Luis DA et al, Ann Nutr Metab 50: 354-. Other studies have shown that fatty acid binding protein 2(FABP2) genotype and dietary fat absorption are associated with moderate carbohydrate intake (Marin et al, Am J Clin Nutr 82: 196-.

Polymorphism of peroxidase proliferation factor-activated receptor-gamma (PPARG) rsl801282 (C/G; Prol2 Ala).

Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors. Peroxidase proliferation factor-activated receptor-gamma (PPARG) is abundantly expressed in adipocytes and plays a key role in adipogenesis, lipid metabolism and development of type 2diabetes. Mice that knock out the peroxidase proliferation factor activated receptor-gamma (PPARG) are unable to produce normal adipose tissue, and, when fed a high-fat diet, have reduced weight gain and do not produce insulin resistance (Jones et al, PNAS 102: 6207-. The 12AIa variant is associated with a reduced binding affinity for peroxidase proliferation factor-activated receptor (PPAR) response factors in the receptor and its target gene, and thus, the ability of the variant to modulate the expression of the target gene is reduced (Deeb et al, Nat Genet 20: 284-287, 1998) (Deeb et al, 1998, published on "Nature genetics" No. 20, page 284-287). Based on the 2006 map of Obesity (Rankine et al, Obesity 14: 529-.

One large transverse study, Quebec Family Study (QFS) (Robitaille et al, Clin Genet 63: 109-116, 2003(Robitaille et al, published in 2003 on "clinical Gene" page 63, 109-116) shows that subjects carrying the 12 proline allele are more likely to respond to fat mass in the daily diet. A similar study (Memisoglu et al, Human Molecular Genetics 12: 2923-. In the 12 alanine vector, this relationship between dietary fat intake and Body Mass Index (BMI) could not be observed, again suggesting that the 12 proline/subject is more sensitive to the amount of fat in the daily diet. Finnish Diabetes prevention studies provide strong evidence for genetic differences in dietary intervention responses (Lindi et al, Diabetes 51: 2581-2586, 2002(Lindi et al, 2002, Vol. 51-2581-2586 of "Diabetes"). After 3 years of dietary and exercise intervention, the body weight loss (-8.3 kg) was greater in the 12 alanine/proline subjects than in the proline 12 alanine subjects (-4.0 kg), and greater than in the 12 proline/proline subjects (-3.4 kg). Studies in overweight and obese women showed no difference in weight loss in 12 proline/proline and 12 alanine/carrier after 6 months of low calorie diet, but later (one year) the weight recovery in women carrying the alanine allele was greater than in women with the 12 proline allele homoconjugate. In response to this intervention, alanine vectors showed a more increased insulin sensitivity and fasting carbohydrate oxidation, as well as a marked decrease in fasting lipid oxidation (Nicklas et al, Diabetes 50: 2172-2176, 2001(Nicklas et al, 2001 at 2172-2176 page 50 of "Diabetes").

The 12 proline/proline body (the most common genotype) is most sensitive to the amount of fat in the daily diet, is more resistant to weight loss and has an increased risk of developing diabetes. For this gene, evidence of gene-diet interactions is strong. In line with the findings from the daily dietary intervention studies, which demonstrate that the 12 alanine carriers have better metabolic adaptation in storing and manipulating fat, the studies show that after intervention an increased Body Mass Index (BMI), greater weight loss and better insulin sensitivity and a reduced risk of developing diabetes are produced. Thus, consistent with the results of the study, the 12 proline allele is a high risk allele.

Polymorphisms of beta-2adrenergic receptor (ADRB2) rs1042713 (G/A; arginine 16 glycine) and beta-2adrenergic receptor (ADRB2) rs1042714 (C/G; Gln27Glu)

The β -2adrenergic receptor (ADRB2) is the predominant form of receptor expressed in adipocytes and plays a major role in the breakdown of fat from adipocytes under the influence of catecholamines to produce energy. Several polymorphisms of the gene that can lead to amino acid changes have been identified, of which arginine 16 glycine and glutamine 27glutamic acid (Gln27Glu) polymorphisms are the most common among caucasians, and a number of investigations on obesity have been conducted. These two polymorphisms are in a strong linkage imbalance (Meirhaeghe et al, Intl J Obesity 24: 382-87, 2000(Meirhaeghe et al, published in 2000 at "world J. Obesity" No. 24, pp. 382-387)). Recombinant expression of these receptors in Chinese hamster fibroblasts in vitro studies have shown the functional impact of these two polymorphisms (Green et al, Biochemistry 33: 9414-9419, 1994(Green et al, 1994, published in "Biochemistry" stage 33, page 9414-9419)). The 16 glycine (16Gly) allele is associated with enhanced downregulation of β -2adrenergic receptor (ADRB2) expression by agonist (isopropyl alcohol ester) treatment, and 27glutamic acid (27Glu) is associated with increased (i.e., resistant to downregulation) β -2adrenergic receptor (ADRB2) expression compared to their respective normal alleles. Interestingly, the binding of the two mutant alleles described above (16 glycine (16Gly) and 27glutamic acid (27Glu)) resulted in increased down-regulation of receptor production. Based on The recent obesity gene profile (Rankine et al, The human obesity gene map: The 2005update. obesitivity 14: 529-. Some studies have shown sex differences in the risk of developing obesity in patients with these polymorphisms (22.Hellstrom et al, J Intern Med 245: 253-.

Many studies have shown that the 27glutamic acid (27Glu) allele is positively associated with abdominal obesity (Lange et al, Int J Obes (Lond) 29: 449-. Longitudinal studies showed that subjects carrying the 16 glycine (16Gly) allele had higher weight gain from childhood to adulthood (Ellsworth et a1.Int J inserts Relat MetabDisord 26: 928-.

An increased risk of obesity (OR ═ 2.56) was observed in 27 glutamine/glutamic acid women with high carbohydrate intake (> 49% of total energy intake), but no relationship was observed in 27 glutamine/glutamine women (Martinez et al, J Nutr 133: 2549-. Sometimes, the allele interpretation and selection of dietary patterns for determining the best polymorphic allele comes from the opposite intervention (overfeeding) study results and the opposite allele is selected. For example, a concurrent overfeeding study (1000 kcal/day over a 100 day period) was performed on male zygotic twins, which showed that 27 glutamine/glutamine subjects gained more weight and subcutaneous fat than subjects carrying the 27glutamic acid (27Glu) allele (Ukkola et al, Int JObes Relat Metab disease 25: 1604-1608, 2001(Ukkola et al, 2001 at "metabolic disease-related Observation" p. 25 1604-1608). A 24-month weight loss program (low calorie diet (1,600 kcal/day) and one hour daily aerobic exercise) was performed in overweight japanese men and this study showed that men carrying the 16 glycine (16Gly) allele were often resistant to weight loss (defined as less than 10% change in Body Mass Index (BMI); n ═ 81) and that these men recovered weight after 6 months of successful weight loss (Masuo et ah, Circulation 111: 3429-. Women who prefer activity during leisure time and are carriers of the 27Glu allele have a higher Body Mass Index (BMI) than non-carriers, indicating that these women may be more resistant to weight loss (Corbalan et al, Clin Genet 61: 305-307, 2002).

Adrenergic beta-3 receptor (ADRB3) rs4994 (C/T; Arg64Trp) polymorphism

Adrenergic beta-3 receptor (ADRB3) is involved in white adipose tissue lipolysis regulation processes and is expressed mainly in visceral adipose tissue, a fat pool closely related to metabolic complications associated with obesity. In vitro experiments on isolated adipocytes have shown that mutations lead to lipolytic degeneration in response to specific agonists in cells carrying the 64 arginine allele (Umekawa et al, Diabetes 48: 117-120, 1999(Umekawa et al, 1999, published on page 117-120 of "Diabetes" 48). It has been found that a haploid composed of three variants in the adrenergic beta-3 receptor (ADRB3) gene, including the 64 arginine variant, is capable of increasing the Body Mass Index (BMI) (n ═ 208) and a 10-fold reduction in visceral adipocyte sensitivity (lipolysis induction) to selective beta 3-receptor agonists (Hoffstedtet al, Diabetes 48: 203-205, 1999(Hoffstedt et al, published on "Diabetes" 48 th stage 203-205 page 1999)). These three variants are in linkage disequilibrium, suggesting that the 64 arginine variant is associated with reduced receptor function. A total of 29 studies have shown a relationship between the adrenergic beta-3 receptor (ADRB3) gene and obesity. Meta-analysis (Meta-analysis) was performed on 31 studies in subjects over 9000 and showed that carriers of the 64 arginine variant had a higher Body Mass Index (BMI) (average 0.30 kg/m higher) compared to 64 tryptophan/tryptophan homozygote subjects (F ujisawa et al, J clin endocrinol Metab 83: 2441-. It was also shown from the results of 22 studies on subjects exceeding 6500 (mainly Japanese) that carriers of the 64 arginine variant had a higher Body Mass Index (BMI) than non-carriers (average 0.26 kg/m higher) (Kurokawa et al, Obes Res 9: 741. sup. 745, 2001(Kurokawa et al, 2001, published on "Observation study" No.9, page 741. sup. 745)).

Case control studies (158 obese subjects, 154 normal heavy subjects) showed that 64 arginine carriers (higher Body Mass Index (BMI)) had an increased risk of developing obesity (OR ═ 2.98) only in quiescent subjects, but not in active subjects, with no genotype difference in Body Mass Index (BMI) observed (Marti et al, Diabetes Obes metals 4: 428-. Intervention treatment was carried out for 3 months in 61 obese women suffering from type 2Diabetes, in combination with a low calorie diet and exercise, and the results showed less weight loss (4.6 kg versus 8.3 kg) and less weight density loss (1.9 kg/m versus 3.4 kg/m) in women with the 64 arginine variant compared to 64 tryptophan/tryptophan women (Sakane et al, Diabetes Care 20: 1887-charge 1890, 1997(Sakane et al, published on page 1887-charge 1890 of "Diabetes Care" stage 20, 1997)). A study was carried out on 76 climacteric women who were subjected to 3 months of intervention therapy in combination with exercise and diet, and as a result, 48% of women carrying the 64 arginine variant were found to have weight loss, while 69% of women not containing the variant had weight loss (Shiwaku et al, Int J Obes Relat Metab disorder 27: 1028-. These two studies demonstrate that this variant is associated with difficulty in weight loss through diet and exercise. A study (Phares et al, Obes Res 12: 807-. This result showed an opposite allelic response to exercise, and the level of exercise in this study was a more vigorous, directed endurance exercise. The explanation of genetic differences in motor responses has become more complex in many studies, since obesity status may become a confounding factor, masking the modest effect of variants on energy expenditure (Tcherof et al, Diabetes 48: 1425-1428, 1999 (Tcherof et al, 1999 in "Diabetes" stage 48, 1425-1428).

Thus, according to some embodiments, provided herein is a method of identifying a metabolic genotype in a subject, comprising identifying a genotype in the subject based on one or more (i.e., 2, 3, or 4) of a fatty acid binding protein 2(FABP2) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) site, an adrenergic beta-3 receptor (ADRB3) site, and/or a beta-2adrenergic receptor (ADRB2) site. According to some embodiments, provided herein are methods of identifying a genotype of a subject's metabolism, comprising identifying the subject's genotype using a subject's genotype with one or more (i.e., 2, 3, 4, or 5) fatty acid binding protein 2(FABP2) (rsl 799883; G/a) site, a peroxidase proliferation factor-activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, there is provided a method of identifying a single polymorphic metabolic genotype in a subject, comprising identifying the genotype based on a metabolic gene allele selected from the group consisting of a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, there is provided a method of identifying a complex metabolic genotype in a subject, comprising identifying the genotype based on at least two metabolic gene alleles selected from the group consisting of a fatty acid binding protein 2(FABP2) (rsl 799883; G/a) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, there is provided a method of identifying a complex metabolic genotype in a subject, comprising identifying the genotype based on at least three metabolic gene alleles selected from the group consisting of a fatty acid binding protein 2(FABP2) (rsl 799883; G/a) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, there is provided a method of identifying a metabolic genotype in a subject, comprising identifying a composite polymorphic genotype based on at least four metabolic gene alleles selected from the group consisting of a fatty acid binding protein 2(FABP2) (rsl 799883; G/a) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; a/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, there is provided a method of identifying a metabolic genotype in a subject, comprising identifying a composite polymorphic genotype based on metabolic gene alleles of each of a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor-activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

The subject single polymorphism metabolic genotype and/or the genotypic results of complex metabolism may be classified according to their relationship to risk of weight management, including those that constitute "reduced responsiveness" or "increased responsiveness" to daily dietary and/or exercise intervention, 2) biomarkers associated with clinical outcome or health, 3) intervention mode selection and weight management, and 4) incidence of each genotype. Tables 1 and 2 shown below define alleles for certain metabolic genotypes and explain the risk of increased sensitivity to certain metabolic disorders/parameters.

Table 1: subject metabolic genes/polymorphisms

Freq ═ population frequency, white race frequency determined using quebec family research (QFS) data

Table 2: subject sensitivity table based on metabolic genotype

BMI (body mass index), TGs (triglyceride), abd fat (abdominal fat), BS (blood glucose), TNFa (tumor necrosis factor α), RMR (resting metabolic rate), HDL (high density lipoprotein)

Effects of metabolism, nutrition and exercise

According to some embodiments, provided herein are methods and kits for measuring blood lipid levels in a subject for selecting or screening the subject for an appropriate treatment or dietary intervention or lifestyle change. The present invention provides methods for measuring high density lipoproteins, low density lipoproteins, and/or triglycerides in a subject. When screened to have low levels of high density lipoproteins, i.e., about 40 mg/dl or less in males and 50 mg/dl or less in females, or high levels of low density lipoproteins, i.e., greater than about 100 mg/dl, or high levels of triglycerides, i.e., greater than about 150 mg/dl, or any combination thereof, the subject is considered to have a distorted lipid profile or dyslipidemia (dyslipemia).

According to some embodiments, the lower level of high density lipoprotein is 20-60 mg/dl or 50-59 mg/dl or 40-49 mg/dl or 30-39 mg/dl or < 30 mg/dl; higher levels of low density lipoprotein are 100- > 190 mg/dl or 100-129 mg/dl or 130-159 mg/dl or 160-190 mg/dl or > 190 mg/dl; and high levels of triglycerides are 150- > 500 mg/dl or 150-.

According to some embodiments, subjects are selected for a clinical trial to test their response to weight management strategies, or therapeutic interventions, the trial comprising identifying subjects by their allelic profile and/or composite genotype of the invention and predicting their response to a recommended treatment/diet/lifestyle or combination thereof based on their predicted high density lipoprotein, or low density lipoprotein or triglyceride levels.

According to some embodiments, provided herein are methods and kits for screening subjects for a weight management clinical trial, wherein subjects with insufficient body weight have a Body Mass Index (BMI) < 18.5; overweight subjects have a Body Mass Index (BMI) in the range of 25-29.9, obese subjects have a Body Mass Index (BMI) of 30-39.9, and a Body Mass Index (BMI) > 40.0 is considered extremely obese. Identifying metabolic genotypes in these subjects may provide a means for health professionals to study the difficulty of reducing the Body Mass Index (BMI) of a subject with a BMI of 25 to 22 using only a low calorie diet.

Table 3 provides the incidence of certain metabolic genotypes in different ethnic groups.

Table 3: genotype/risk between different ethnicitiesIncidence of mode

The combination of these genetic changes affects 1) what the subject will respond to certain essential nutrients in their daily diet, and 2) the different trends in energy metabolism that ultimately affect their ability to maintain or lose weight through exercise. Determining the metabolic genotype will help healthy subjects identify the genetic risk of the reverse weight management problem, even if it has not already occurred. Earlier knowledge of gene-related risks can help to formulate individual health decisions (nutrition, lifestyle), ensure future health, and provide guidance on how to best prioritize subject nutrition and lifestyle choices for better management of body weight and body structure.

Information obtained from a subject's metabolic genotype may be used to predict a subject's genetic risk for adverse weight management problems. The subject genotype may be used to assess risk and select an appropriate treatment/diet regimen or recommended lifestyle. Identification of the subject's genotype may be used to pair the subject with a therapeutic or nutritional or replacement lifestyle or any combination of two or three to design a strategy to achieve and/or maintain weight loss. Generally, in weight loss management programs, the allelic patterns of one or more metabolic genes in a subject may be used to classify the subject's response to dietary macronutrients and energy restriction with or without exercise. Thus, an individual's weight management program may be selected based on the predicted response of the subject. For example, a weight management program may classify a subject's metabolic genotype into a nutritional category series and an athletic category series according to the subject's propensity to respond to certain primary nutrient elements and exercise levels. The nutritional species, sports species, or combination thereof is selected according to the genetic profile of the subject.

According to some embodiments, there is provided a method of selecting an appropriate treatment/dietary regimen or recommended lifestyle for a subject, the method comprising determining a genotype of the subject based on any four polymorphic sites selected from the group consisting of a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor- γ (PPARG) (rsl 801282; C/G) site, a β -3 adrenergic receptor (ADRB3) (rs 4994; C/T) site, a β -2adrenergic receptor (ADRB2) (rs 1042713; A/G) site, and/or a β -2adrenergic receptor (ADRB2) (rs 1042714; C/G) site, wherein the genotype of the subject determined based on the above sites provides information on the subject's increased sensitivity to adverse management problems, and select an appropriate treatment/diet regimen or recommended lifestyle based on the subject's sensitivity to adverse weight management problems.

According to some embodiments, subjects carrying the combined genotypes of fatty acid binding protein 2(FABP2) (rs1799883)1.1, peroxidase proliferation factor activated receptor- γ (PPARG) (rs1801282)1.1, β -2adrenergic receptor (ADRB2) (rs1042714)1.1 and β -2adrenergic receptor (ADRB2) (rsl042713)2.2 and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 are predicted to be able to respond to: a low-fat or low-carbohydrate, calorie-restricted diet; periodic movements or a combination of both.

According to some embodiments, subjects carrying a fatty acid binding protein 2(FABP2) (rs1799883)1.1 or 1.2 and peroxidase proliferation factor activated receptor-gamma (PPARG) (rs1801282)1.1 complex genotype, and an additional beta-2adrenergic receptor (ADRB2) (rsl042714)1.1, 1.2, or genotype 2.2 binding to beta-2adrenergic receptor (ADRB2) (rsl042713)2.2 and adrenergic beta-3 receptor (ADRB3) (rs4994)1.1 are predicted to be able to respond to: a low-fat, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, a subject carrying a complex genotype of fatty acid binding protein 2(FABP2) (rs1799883)1.2 or 2.2 and/or β -2adrenergic receptor (ADRB2) (rsl042714)1.2 or 2.2 binding to β -2adrenergic receptor (ADRB2) (rs1042713)2.2 and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 is predicted to be able to pair: a low-fat, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, subjects carrying a peroxidase proliferation factor activated receptor-gamma (PPARG) (rs1801282) 1.2 or 2.2 and a fatty acid binding protein 2(FABP2) (rsl799883)1.1 or 1.2 genotype binding to the beta-2adrenergic receptor (ADRB2) (rs1042713)2.2 and the adrenergic beta-3 receptor (ADRB3) (rs4994)1.1 are predicted to be able to respond to: a low-fat, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, subjects carrying a binding genotype of fatty acid binding protein 2(FABP2) (rsl799883)1.1 and peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.1 binding to one beta-2adrenergic receptor (ADRB2) (rsl042713)1.2 or 1.1 or one adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 are predicted to be able to: low fat or low carbohydrate, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, a subject carrying a binding genotype of one of fatty acid binding protein 2(FABP2) (rsl799883)1.1 or 1.2 and peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.1 in combination with one of beta-2adrenergic receptor (ADRB2) (rsl042713)1.1, 1.2 or 2.2 or one of beta-2adrenergic receptor (ADRB2) (rsl042713)1.1 or 1.2 or one of adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 is predicted to be able to bind to: low fat, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, a subject carrying a binding genotype for a combination of one of the peroxidase proliferation factor activated receptors-gamma (PPARG) (rsl801282)1.2 or 2.2 with one of the beta-2adrenergic receptor (ADRB2) (rsl042713)1.2 or 2.2 with one of the beta-2adrenergic receptor (ADRB2) (rsl042713)1.1 or 1.2, or one of the adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 is predicted to be able to: low carbohydrate, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, a subject carrying a binding genotype for the binding of one of the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.2 or 2.2 to one of the fatty acid binding protein 2(FABP2) (rsl799883)1.1 or 1.2 to one of the beta-2adrenergic receptor (ADRB2) (rsl042713)1.1 or 1.2, or one of the adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 is predicted to be able to: low carbohydrate, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, the treatment/diet regimen comprises administration of a nutraceutical (nutraceutical).

According to some embodiments, the method further comprises classifying the subject according to possible benefits of treatment/diet regimen or lifestyle changes.

According to some embodiments, the low fat diet of the above method provides no more than about 35 percent of total calories.

According to some embodiments, the low carbohydrate diet of the above method provides less than about 50 percent of the total calories.

According to some embodiments, the calorie-restricted diet of the above method restricts total calories to less than 95% of the subject's weight management level.

According to some embodiments, there is provided a method of identifying a metabolic genotype of a subject, the method comprising: the subject genotype is recognized by at least three of the fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, the adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, the beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or the beta-2adrenergic receptor (ADRB2) (rsl 042714; C/G) site.

According to some embodiments, there is provided a method of identifying a metabolic genotype of a subject, the method comprising: the subject genotype is recognized based on at least four of the fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, the adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, the beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or the beta-2adrenergic receptor (ADRB2) (rsl 042714; C/G) site.

According to some embodiments, provided herein is a method of selecting an appropriate treatment/dietary regimen or recommended lifestyle for a subject, comprising: a) determining the genotype of the subject based on any four polymorphic sites selected from the group consisting of: a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rsl 042714; C/G) site; and b) classifying the subject into a nutritional category and/or a sports category based on the benefits expected to be obtained by the subject, wherein the nutritional category is selected from a low fat diet; a geo-carbohydrate diet; a high protein diet; and a calorie-restricted diet, and wherein the exercise category is selected from: performing mild exercise; normal movement; and vigorous exercise.

According to some embodiments, there is provided a method of selecting an appropriate treatment/dietary regimen or recommended lifestyle for a subject, the method comprising: a) determining the genotype of the subject based on at least 2 alleles selected from the group consisting of allele 1 (alanine or G) of fatty acid binding protein 2(FABP2) (rsl799883), allele 2 (threonine or one) of fatty acid binding protein 2(FABP2) (rsl799883), allele 1 (proline or C) of peroxisome proliferator-activated receptor-gamma (PPARG) (rsl801282), allele 2 (alanine or G) of peroxisome proliferator-activated receptor-gamma (PPARG) (rsl801282), allele 1 (tryptophan or T) of adrenergic beta-3 receptor (ADRB3) (rs4994), allele 2 (arginine or C) of adrenergic beta-3 receptor (RB AD 3) (rs 94), allele 1 (glycine or G) of beta-2adrenergic receptor (ADRB2) (rsl042713 271043), allele 1 (glycine or G), Beta-2adrenergic receptor (ADRB2) (rsl042713) allele 2 (arginine or A), beta-2adrenergic receptor (ADRB2) (rslO42714) allele 1 (glutamine or C) and beta-2adrenergic receptor (ADRB2) ((rslO42714) allele 2 (glutamic acid or G); wherein the allelic profile is present in a manner that predicts the subject's response to daily diet and/or exercise, and b) selecting a treatment/diet profile or recommended lifestyle based on the subject's predicted response to daily diet and/or exercise.

According to some embodiments, subjects carrying a binding genotype for fatty acid binding protein 2(FABP2) (rsl799883)1.1 (alanine/alanine or G/G), peroxidase proliferation factor activated receptor- γ (PPARG) (rsl801282)1.1 (proline/proline or C/C), β -2adrenergic receptor (ADRB2) (rslO42714)1.1 (glutamine/glutamine or C/C) and β -2adrenergic receptor (ADRB2) (rsl042713)2.2 (arginine/arginine or a/a) and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 (tryptophan/tryptophan or T/T) are predicted to be able to respond to: a low-fat or low-carbohydrate, calorie-restricted diet; periodic movements or a combination of both.

According to some embodiments, a subject carrying fatty acid binding protein 2(FABP2) (rsl799883)1.1 (alanine/alanine or G/G) or 1.2 (alanine/threonine or G/a) and the peroxisome proliferator activated receptor- γ (PPARG) (rsl801282)1.1 (proline/proline or C/C), and β -2adrenergic receptor (ADRB2) (rslO42714)1.1 (glutamine/glutamine or C/C), 1.2 (glutamine/glutamic acid or C/G), or 2.2 (glutamic acid/glutamic acid or G/G) and β -2adrenergic receptor (ADRB2) (rsl042713)2.2 (arginine/arginine or a/a) and adrenergic β -3 receptor (ADRB3) (rs 8594) 1.1 (tryptophan/tryptophan or T/T) can be predicted to be paired with a binding gene of the type : a low-fat or low-carbohydrate, calorie-restricted diet; periodic movements or a combination of both.

According to some embodiments, subjects carrying a binding genotype of one of the peroxidase proliferation factor activated receptors-gamma (PPARG) (rsl801282)1.2 (proline/alanine (C/G) or 2.2 (alanine/alanine or G/G) and/or beta-2adrenergic receptor (ADRB2) (rslO42714)1.2 (glutamine/glutamic acid or C/G) or 2.2 (glutamic acid/glutamic acid or G/G) with beta-2adrenergic receptor (ADRB2) (rsl042713)2.2 (arginine/arginine or a/a) and adrenergic beta-3 receptor (ADRB3) (rs4994)1.1 (tryptophan/tryptophan or T/T) are predicted to be able to respond to: a low carbohydrate, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, a subject carrying a peroxidase proliferation factor activated receptor- γ (PPARG) (rsl801282)1.2 (proline/alanine (C/G) or 2.2 (alanine/alanine or G/G) and one of fatty acid binding proteins 2(FABP2) (rs1799883)1.1 (alanine/alanine or G/G) or 1.2 (alanine/threonine or G/a) with a binding genotype for β -2adrenergic receptor (ADRB2) (rsl042713)2.2 (arginine/arginine or a/a) and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 (tryptophan/tryptophan or T/T) is predicted to be able to: a low carbohydrate, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, subjects carrying a binding genotype of fatty acid binding protein 2(FABP2) (rsl799883)1.1 (alanine/alanine or G/G) and peroxidase proliferation factor activated receptor- γ (PPARG) (rsl801282)1.1 (proline/proline or C/C), and one of β -2adrenergic receptor (ADRB2) (rsl042713 271043) 1.2 (glycine/arginine or G/a) or 2.2 (arginine/arginine or a/a), or adrenergic β -3 receptor (ADRB3) (rs4994)1.2 (arginine/tryptophan or T/C) or 2.2 (arginine/arginine or C/C) are predicted to be able to bind to: low fat or low carbohydrate, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, the polypeptide carries fatty acid binding protein 2(FABP2) (rsl799883)1.1 (alanine/alanine or G/G) or 1.2 (alanine/threonine or G/A) and the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.1 (proline/proline or C/C), and one of the beta-2adrenergic receptors (ADRB2) (rsl042714)1.1 (glutamine/glutamine or C/C), 1.2 (glutamine/glutamic acid or C/G) or 2.2 (glutamic acid/glutamic acid or G/G)) and one of the beta-2adrenergic receptors (ADRB2) (rs1042713)1.1 (glycine/glycine or G/G) or 1.2 (glycine/arginine or G/A), or adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 (arginine/tryptophan or T/C) or 2.2 (arginine/arginine or C/C) is predicted to be able to pair: low fat, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, subjects carrying a complex genotype of a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282) one of 1.2 (proline/alanine or C/G) or 2.2 (alanine/alanine or G/G) and/or beta-2adrenergic receptor (ADRB2) (rslO42714)1.2 (glutamine/glutamic acid or C/G) or 2.2 (glutamic acid/glutamic acid or G/G) in combination with one of beta-2adrenergic receptor (ADRB2) (ADRB 1042713)1.1 (glycine/glycine or G/G) or 1.2 (glycine/arginine or G/a) or adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 (tryptophan/arginine or T/C) or 2.2 (arginine/arginine or C/C) are pre-treated The meter can be used for: low carbohydrate, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, a subject carrying a complex genotype of one of the peroxidase proliferation factor activated receptors- γ (PPARG) (rsl801282)1.2 (proline/alanine or C/G) or 2.2 (alanine/alanine or G/G) and fatty acid binding protein 2(FABP2) (rs1799883)1.1 (alanine/alanine or G/G) or 1.2 (alanine/threonine or G/a) in combination with one of the β -2adrenergic receptors (ADRB2) (rs1042713)1.1 (glycine/glycine or G/G) or 1.2 (glycine/arginine or G/a) or one of the adrenergic β -3 receptors (rb 3) (rs 94)1.2 (tryptophan/arginine or T/C) or 2.2 (arginine/arginine or C/C) is predicted to be able to: low carbohydrate, calorie restricted diets react. According to some embodiments, the subject is further predicted to be insufficiently responsive to periodic exercise.

According to some embodiments, there is provided a method of predicting a subject's genetic risk for an adverse weight management problem, the method comprising: detecting a genetic polymorphism pattern comprising at least two alleles selected from the group consisting of allele 1 (alanine or G) of fatty acid binding protein 2(FABP2) (rsl799883), allele 2 (threonine or A) of fatty acid binding protein 2(FABP2) (rsl799883), allele 1 (proline or C) of peroxisome proliferator-activated receptor-gamma (PPARG) (rsl801282), allele 2 (alanine or G) of peroxisome proliferator-activated receptor-gamma (PPARG) (rsl801282), allele 1 (tryptophan or T) of adrenergic beta-3 receptor (ADRB3) (rs4994), allele 2 (arginine or C) of adrenergic beta-3 receptor (RB AD 3) (rs 94), allele 1 (glycine or G) of beta-2adrenergic receptor (ADRB2) (rs1042713), Beta-2adrenergic receptor (ADRB2) (rs1042713) allele 2 (arginine or A), beta-2adrenergic receptor (ADRB2) (rslO42714) allele 1 (glutamine or C) and beta-2adrenergic receptor (ADRB2) (rsl042714) allele 2 (glutamic acid or G), wherein the presence of the pattern of genetic polymorphisms is predictive of a subject's response to daily diet and/or exercise.

According to some embodiments, provided herein is a kit comprising: a) an agent for determining the genotype of a subject based on any four polymorphic sites selected from the group consisting of: a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rsl 042713; A/G) site; and the beta-2adrenergic receptor (ADRB2) (rsl 042714; C/G) site; and b) instructions for determining the subject's metabolic genotype, and means for classifying the subject as a nutritional category and/or an exercise category based on the benefits expected to be obtained by the subject, wherein the nutritional category is selected from a low fat diet; a geo-carbohydrate diet; a high protein diet; and a calorie-restricted diet, and wherein the exercise category is selected from: performing mild exercise; normal movement; and vigorous exercise.

According to some embodiments, the kit further classifies the subject according to possible benefits of treatment/diet regimens or lifestyle changes.

According to some embodiments, the kit comprises reagents for genotyping a subject, a subject carrying a binding genotype for fatty acid binding protein 2(FABP2) (rsl799883)1.1, peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.1, beta-2adrenergic receptor (ADRB2) (rslO42714)1.1 and beta-2adrenergic receptor (ADRB2) (rsl042713)2.2, and adrenergic beta-3 receptor (ADRB3) (rs4994)1.1 is predicted to be able to: a low-fat or low-carbohydrate, calorie-restricted diet; periodic movements or a combination of both.

According to some embodiments, the kit comprises reagents for genotyping a subject, a subject carrying a combined genotype of one of fatty acid binding protein 2(FABP2) (rsl799883)1.1 or 1.2 and peroxidase proliferation factor activated receptor- γ (PPARG) (rsl801282)1.1, and one of β -2adrenergic receptor (ADRB2) (rslO42714)1.1, 1.2 or 2.2 and β -2adrenergic receptor (ADRB2) (rsl042713)2.2 and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 is predicted to be capable of binding to: a low-fat, calorie restricted diet; normal movement or a combination of both.

According to some embodiments, the kit comprises reagents for genotyping a subject, a subject carrying a binding genotype for one of the peroxisome proliferator activated receptor- γ (PPARG) (rsl801282)1.2 or 2.2 and/or β -2adrenergic receptor (ADRB2) (rslO42714)1.2 or 2.2 with β -2adrenergic receptor (ADRB2) (rslO42713)2.2 and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 is predicted to be able to: a low carbohydrate, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, the kit comprises reagents for genotyping a subject carrying a binding genotype for one of the peroxisome proliferator activated receptor- γ (PPARG) (rsl801282)1.2 or 2.2 and fatty acid binding protein 2(FABP2) (rs1799883)1.1 or 1.2, with β -2adrenergic receptor (ADRB2) (rslO42713)2.2 and adrenergic β -3 receptor (ADRB3) (rs4994)1.1 that is predicted to be capable of: a low carbohydrate, calorie restricted diet; periodic movements or a combination of both.

According to some embodiments, the kit comprises reagents for genotyping a subject, a subject carrying fatty acid binding protein 2(FABP2) (rsl799883)1.1 and peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.1, a binding genotype with one of beta-2adrenergic receptor (ADRB2) (rslO42713)1.2 or 1.1 or one of adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 is predicted to be able to: low fat, low carbohydrate, calorie restricted diets react.

According to some embodiments, the kit comprises reagents for genotyping a subject, a subject carrying a fatty acid binding protein 2(FABP2) (rsl799883)1.1 or 1.2 and a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.1, a binding genotype to one of the beta-2adrenergic receptor (ADRB2) (rs1042714)1.1, 1.2, or 2.2 or the beta-2adrenergic receptor (ADRB2) (rslO42713)1.1 or 1.2 or the adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 is predicted to be capable of binding to: low fat, calorie restricted diets react.

According to some embodiments, the kit comprises reagents for genotyping a subject carrying a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.2 or 2.2 and/or one of the β -2adrenergic receptors (ADRB2) (rs1042714) 1.2 or 2.2, a binding genotype with one of the β -2adrenergic receptors (ADRB2) (rslO42713)1.1 or 1.2 or one of the adrenergic β -3 receptors (ADRB3) (rs4994)1.2 or 2.2 is expected to be able to target: low carbohydrate, calorie restricted diets react.

According to some embodiments, the kit comprises reagents for genotyping a subject, a subject carrying a binding genotype for one of the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282)1.2 or 2.2 and/or one of the fatty acid binding protein 2(FABP2) (rs1799883)1.1 or 1.2, and one of the beta-2adrenergic receptor (ADRB2) (rslO42713)1.1 or 1.2 or the adrenergic beta-3 receptor (ADRB3) (rs4994)1.2 or 2.2 is expected to be able to: low carbohydrate, calorie restricted diets react.

According to some embodiments, provided herein is a kit comprising: reagents and instructions for determining a subject's metabolic genotype comprising identifying the subject's genotype based on at least four of a fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, a peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, an adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, a beta-2adrenergic receptor (ADRB2) (rs 1042713; A/G) site, and/or a beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

According to some embodiments, provided herein is a kit comprising: a kit of parts for determining the genotype of a subject's metabolism comprising identifying the subject's genotype based on at least three of the fatty acid binding protein 2(FABP2) (rsl 799883; G/A) site, the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282; C/G) site, the adrenergic beta-3 receptor (ADRB3) (rs 4994; C/T) site, the beta-2adrenergic receptor (ADRB2) (rs 1042713; A/G) site, and/or the beta-2adrenergic receptor (ADRB2) (rs 1042714; C/G) site.

Nutrient species

Nutritional categories are generally distinguished by the amount of primary nutrients (i.e., fat, carbohydrate, protein) that a subject is recommended to eat based on the subject's metabolic genotype. The main goal of selecting an appropriate treatment/diet regimen or recommended lifestyle for a subject is to match the subject's metabolic genotype with the nutritional species to which the subject is most likely to respond. Nutritional categories are typically expressed in terms of the relative amounts of the primary nutrient elements provided in the subject's daily diet or in terms of caloric restriction (e.g., restricting the total amount of calories received by the subject and/or restricting the amount of calories received by the subject from a particular primary nutrient element). For example, nutritional categories may include, but are not limited to: 1) a low fat, low carbohydrate diet; 2) a low fat diet; or 3) a low carbohydrate diet. Alternatively, the nutritional categories may be distinguished by restrictions on certain primary nutrients that the subject recommends to eat based on the subject's metabolic genotype two. For example, the nutritional categories may be expressed as: 1) balanced or calorie restricted diets; 2) a fat-restricted diet, or 3) a carbohydrate-restricted diet.

Subjects carrying a metabolic genotype that can respond to a fat-restricted or low-fat diet tend to absorb more dietary fat into the body and have a slower metabolic profile. They have a more pronounced tendency towards weight gain. Clinical studies have shown that these subjects can reach healthy body weight in a shorter time by reducing total dietary fat. Subsequently, they can gain greater success in reducing weight by reducing dietary fat and/or reducing dietary calories. In addition, in reduced calorie diets, saturated fatty acids are replaced with unsaturated fatty acids, which also have beneficial effects on these subjects. Clinical studies have also shown that these dietary changes can improve the body's ability to metabolize sugars and fats.

Subjects carrying metabolic genotypes responsive to carbohydrate restriction or low carbohydrate diets tend to be more susceptible to weight gain from excessive carbohydrate intake. These subjects are better able to lose weight by reducing the carbohydrate content of the calorie diet. Subjects carrying this genetic pattern are prone to obesity and have difficulty regulating blood glucose if high carbohydrates are ingested in the daily diet, for example, when the daily carbohydrate intake exceeds, for example, about 49% of the total calories. It has been shown that reducing carbohydrates can optimize the blood glucose regulation and reduce the risk of further weight gain. If the subject has a diet with highly saturated fatty acids and less monounsaturated fatty acids, the risk of weight gain and elevated blood glucose is correspondingly increased. When total calories are limited, limiting total carbohydrate intake and converting the fat composition in its diet to monounsaturated fatty acids (e.g., a low-calorie fat diet and a low-carbohydrate diet) can provide benefits to these subjects.

Subjects carrying metabolic genotypes that respond to a balance of fat and carbohydrate are not consistently in need of a low fat or low carbohydrate diet. In these subjects, key biomarkers, such as body weight, body fat and blood lipid profiles, respond well to a balanced diet of fat and carbohydrates. For subjects carrying this genetic pattern, when they are interested in weight loss, studies have found that calorie-restricted balanced diets are beneficial in accelerating weight loss and reducing body fat.

A low fat diet is one in which between about 10% and less than 40% of the total calories are provided from fat. According to some embodiments, a low fat diet means that no more than about thirty-five percent (e.g., no more than about 19%, 21%, 23%, 22%, 24%, 26%, 28%, 33%, etc.) of the total calories are provided from fat. According to some embodiments, a low fat diet refers to a diet that provides no more than thirty percent of the total calories from fat. According to some embodiments, a low fat diet means that calories provided from fat do not exceed twenty-five percent of the total calories. According to some embodiments, a low fat diet means that calories provided from fat do not exceed twenty percent of the total calories. According to some embodiments, a low fat diet means that calories provided from fat do not exceed fifteen percent of the total calories. According to some embodiments, a low fat diet means that calories provided from fat do not exceed ten percent of the total calories.

According to some embodiments, a low fat diet refers to a diet having a daily fat intake of between about 10 grams and about 60 grams. According to some embodiments, a low fat diet refers to a diet having a daily fat intake of less than about 50 grams (e.g., less than about 10 grams, 25 grams, 35 grams, 45 grams, etc.). According to some embodiments, a low fat diet refers to a diet having a daily fat intake of less than about 40 grams. According to some embodiments, a low fat diet refers to a diet having a daily fat intake of less than about 30 grams. According to some embodiments, a low fat diet refers to a diet having a daily fat intake of less than about 20 grams.

Fats include saturated fatty acids and unsaturated fatty acids (monounsaturated fatty acids and polyunsaturated fatty acids). According to some embodiments, the diet in which the amount of saturated fat is reduced to less than ten percent calories is a low saturated fat diet. According to some embodiments, the diet in which the amount of saturated fat is reduced to less than fifteen percent calories is a low saturated fat diet. According to some embodiments, the diet in which the amount of saturated fat is reduced to less than twenty percent calories is a low saturated fat diet.

A low Carbohydrate (CHO) diet is a diet in which the carbohydrates provide between about 20% and less than 50% of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about fifty percent (e.g., does not exceed about 20%, 25%, 30%, 35%, 40%, 45%, etc.) of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about forty-five percent of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about forty percent of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about thirty-five percent of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about thirty percent of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about twenty-five percent of the total calories. According to some embodiments, a low Carbohydrate (CHO) diet means that the amount of calories provided by carbohydrates does not exceed about twenty percent of the total calories.

A low Carbohydrate (CHO) diet may refer to a diet capable of limiting the number of grams of carbohydrate in the diet, e.g., an amount of carbohydrate in the diet of between about 20 grams and 250 grams per day. According to some embodiments, a low carbohydrate diet includes no more than about 220 grams of carbohydrates per day (e.g., no more than about 40 grams, 70 grams, 90 grams, 110 grams, 130 grams, 180 grams, 210 grams, etc.). According to some embodiments, a low carbohydrate diet includes no more than about 200 grams of carbohydrates per day. According to some embodiments, a low carbohydrate diet includes no more than about 180 grams of carbohydrates per day. According to some embodiments, a low carbohydrate diet includes no more than about 150 grams of carbohydrates per day. According to some embodiments, a low carbohydrate diet includes no more than about 130 grams of carbohydrates per day. According to some embodiments, a low carbohydrate diet includes no more than about 100 grams of carbohydrates per day. According to some embodiments, a low carbohydrate diet includes no more than about 75 grams of carbohydrates per day.

A calorie-restricted diet or balanced diet refers to a diet that restricts total calories used to below the subject's Weight Maintenance Level (WML), whether or not in preference to certain major nutritional elements. A balanced diet or calorie-restricted diet can reduce the overall calorie intake of a subject by, for example, reducing the subject's overall calorie intake to a level below the Weight Maintenance Level (WML) and not specifically restricting the use of any particular primary nutrient element. Thus, according to some embodiments, the balanced diet may be expressed as a percentage of the subject's Weight Maintenance Level (WML). For example, a balanced diet is a diet that includes a total caloric intake between about 50% to about 100% Weight Maintenance Level (WML). According to some embodiments, a balanced diet refers to a diet that includes a total caloric intake of less than 100% Weight Maintenance Level (WML) (e.g., less than about 99%, 97%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55% Weight Maintenance Level (WML)). Within this structure, a balanced diet enables a healthy or desired balance of the main nutritional elements in the diet and can be: low fat; low saturated fat; a low carbohydrate; low fat and low carbohydrate; or low saturated fat and low carbohydrate. For example, the diet may be a low fat, calorie restricted diet (wherein low fat has the meaning as described above). The diet may be a low carbohydrate, calorie restricted diet (wherein low carbohydrate has the meaning as described above). The diet may be a balanced, calorie-restricted diet (e.g., the relative portion of the primary nutrient elements may be varied, wherein the total calories used is less than the Weight Maintenance Level (WML)). According to some embodiments, a low carbon Diet (carbon: 45%, protein: 20%, fat: 35%) includes Atkins Diet (Atkins Diet), glycaemic Impact Diet (Glycemic Impact Diet), South beach Diet (South beach Diet), Sugar bullet Diet (Sugar bullets Diet), and/or Zone Diet.

According to some embodiments, a low fat diet (carbon: 65%, protein: 15%, fat: 20%) includes a life selection diet (Ornish diet), a Pritikin diet, and/or other commercially available heart health diets.

According to some embodiments, the balanced Diet (carbon: 55%, protein: 20%, fat: 25%) comprises a Best-living Diet (Best Life Diet), a Mediterranean type Diet, a Sonoma Diet, a Volumetrics Eating Diet, a Weight Watchers Diet.

Other low carbohydrate, low fat, balanced diets and calorie restricted diets are well known to those of ordinary skill in the art and, therefore, may be recommended to a subject based on the subject's metabolic genotype and predicted to respond to the calorie restricted diet or other types of diet.

Kind of sports

The type of exercise is generally distinguished by the subject's response to exercise, with reference to the subject's metabolic genotype. For example, the subject may respond to light exercise, moderate exercise, intense exercise, or very intense exercise.

The body, which carries a metabolic genotype that can respond to exercise, can effectively decompose body fat as a response to physical exercise. They tend to respond to exercise, significantly lose weight, and most likely maintain the lost weight. Subjects fall into this category if they respond to mild or moderate exercise.

Compared to subjects carrying other genetic patterns, subjects carrying metabolic genotypes that do not respond much to exercise are less able to break down body fat into energy as a response to physical exercise. In moderate exercise, they lose less weight and body fat than expected. These subjects require more exercise to break down body fat into energy and lose weight. They must also maintain a continuous exercise program to maintain the lost weight.

Mild exercise mainly refers to the subject exercising for 1-3 days per week (taking exercise or exercise). Moderate exercise mainly refers to 3-5 days of exercise (taking exercise or exercise) per week. High activity exercise refers to a subject exercising 6-7 days per week (taking exercise or exercise). Intense exercise or very intense exercise mainly refers to a subject exercising more than once per day on average (e.g., 2 exercises per day). Regular exercise refers to exercise that is at least mild exercise or at least moderate exercise.

More precisely, the activity level can be expressed in terms of a percentage of the basal metabolic rate. For example, factors of the harris-benedict formula or the Katch-McArdle formula may be used as a basis for defining activity levels. Mild exercise, therefore, refers to a recommended level of exercise with the goal of achieving a subject's Total Daily Energy Expenditure (TDEE) between about 125% basal metabolic rate (i.e., about a 25% increase) and less than about 140% basal metabolic rate (e.g., about 128%, 130%, 133%, 135%, 137.5%, etc.). Moderate exercise refers to a recommended level of exercise that is aimed at achieving a Total Daily Energy Expenditure (TDEE) for the subject between about 140% of basal metabolic rate and less than about 160% of basal metabolic rate (e.g., about 142%, 145%, 150%, 155%, 158%, etc.). Strenuous exercise refers to a recommended level of exercise that is aimed at achieving a Total Daily Energy Expenditure (TDEE) of between about 160% of basal metabolic rate and less than about 180% of basal metabolic rate (e.g., about 162%, 165%, 170%, 172.5%, 175%, 178%, etc.). Very strenuous exercise or extremely strenuous exercise refers to a recommended level of exercise that is aimed at achieving a Total Daily Energy Expenditure (TDEE) of the subject between about 180% of basal metabolic rate and less than about 210% of basal metabolic rate (e.g., about 182%, 185%, 190%, 195%, 200%, etc.).

Alternatively, according to some embodiments, "normal motion" generally includes: moderate exercise (moderate exercise is defined as 3.0-5.9METs) 2.5 hours (150 minutes) per week, and "mild exercise" typically includes: moderate exercise less than 2.5 hours per week, and "strenuous exercise" typically includes: intense exercise of about 13METs per week (intense exercise is defined as 6METs or higher). 1MET equals 1 calorie/kg body weight/hour. Total kilocalories consumed by the subject is MET value for exercise x kg unit body weight x hours as time units.

Weight gain and loss depend on a balance between calorie absorption and calorie consumption. When the amount of absorbed calories is greater than the amount of consumed calories, body weight is increased. Conversely, if the amount of absorbed calories is less than the amount of consumed calories, the body weight is reduced. The subject Weight Maintenance Level (WML) refers to the total calorie intake that the subject needs to absorb in order to maintain an existing weight. The Weight Maintenance Level (WML) of a subject may be determined or calculated using any method known in the art. The Weight Maintenance Level (WML) is usually expressed as daily total energy expenditure (TDEE) or estimated energy demand (EER). Although there are technical differences in the meaning of Total Daily Energy Expenditure (TDEE) and estimated energy demand (EER) used in the art, which reflect the way in which a subject's weight maintenance level is calculated, in the context of maintaining their technical differences, these two terms may be used interchangeably in their broad definitions. The Weight Maintenance Level (WML) of the subject may be determined by calculating the Weight Maintenance Level (WML) (e.g., Total Daily Energy Expenditure (TDEE) or Estimated Energy Requirement (EER)) using any method known to those skilled in the art.

On average, for american women, Weight Maintenance Levels (WML) were between 2000-. The average Weight Maintenance Level (WML) for men was high, between 2700-. A more preferred method of calculating Total Daily Energy Expenditure (TDEE) is by using the Harris-Benedict formula or the Katch-McArdle formula, both of which are well known to those of ordinary skill in the art. Briefly, the harris-benedict formula first determines the Basal Metabolic Rate (BMR) of a subject and then calibrates according to exercise level to give the Total Daily Energy Expenditure (TDEE) of the subject. For example, the basal metabolic rate in women can be calculated according to the following formula: BMR_f65.51+ (9.563x kg) + (1.850x cm) - (4.676x age). The basal metabolic rate of males can be calculated by the following formula: BMR_m66.5+ (13.75x kg) + (5.003x cm) - (6.775x age). The basal metabolic rate is then calibrated by multiplying the basal metabolic rate by a factor specified for the particular activity level. The following table provides examples of such factors. The result is Total Daily Energy Expenditure (TDEE) by the subject.

Table 4: kind of sports

Total energy consumption per day (TDEE)

The Katch & McArdle formula is based on the body weight Loss (LBM) of the subject. For example, the basal metabolic rate is calculated according to the following formula: basal metabolic rate (male and female) 370+ (21.6X kg units of Lean Body Mass (LBM)). Since the Katch-McArdle formula yields a Lean Body Mass (LBM), this formula is equally applicable to both men and women. The Total Daily Energy Expenditure (TDEE) was then determined using the motion factor used in the harris-benedict equation (see table above).

Classification

Generally, the subject's metabolic genotype is divided into a single nutritional species and a single sports species. Thus, according to some embodiments, the subject is classified into a nutritional category and an exercise category according to the subject's metabolic genotype. For example, subjects may be classified into one of the following six categories: 1) reacting to fat restriction and to exercise; 2) less responsive to fat restriction and less responsive to exercise; 3) reacting to carbohydrate restriction and reacting to exercise; 4) less responsive to carbohydrate restriction and less responsive to exercise; 5) fat and carbohydrate balance and react to exercise; and 6) fat and carbohydrate balance and are less responsive to exercise.

1) Response to fat restriction and response to exercise: subjects with this genetic pattern absorb more dietary fat into the body and have a slower metabolic action. They have a greater tendency to gain weight. Clinical studies have demonstrated that such subjects are able to reach healthy body weight more quickly by reducing total dietary fat. They can achieve greater success in weight loss through a reduced fat, reduced calorie diet. In addition, replacing saturated fats in a reduced calorie diet with monounsaturated fats can also benefit these subjects. Clinical studies have also shown that these same dietary changes can improve the ability of subjects to metabolize sugars and fats.

The subject with the genetic mode can react to the body movement and effectively decompose the body fat. In response to exercise, these subjects were able to significantly reduce body weight and most likely maintain the reduced body weight. These subjects can also benefit from any level of increased exercise, for example, at least mild exercise or at least moderate exercise.

2) Less responsive to fat restriction and less responsive to exercise; subjects with this genetic pattern absorb more dietary fat into the body and have a slower metabolic action. They have a greater tendency to gain weight. Clinical studies have demonstrated that such subjects are able to reach healthy body weight more quickly by reducing total dietary fat. They can achieve greater success in weight loss through a reduced fat, reduced calorie diet. In addition, replacing saturated fats in a reduced calorie diet with monounsaturated fats can also benefit these subjects. Clinical studies have also shown that these same dietary changes can improve the ability of subjects to metabolize sugars and fats.

Subjects with this genetic pattern have less ability to break down body fat under the influence of exercise than subjects carrying other genetic patterns. Under moderate exercise conditions, they reduced less body weight and body fat than expected. These subjects need to perform more exercise to activate the breakdown of body fat into energy and lose weight. They must maintain a continuous exercise program to keep the weight down at the same time.

3) Response to carbohydrate restriction and response to exercise: subjects with this genetic pattern more readily gain weight gain from excessive carbohydrate intake. They have been able to more successfully lose weight by reducing the amount of carbohydrates in a low calorie diet. Subjects with this genetic pattern are prone to obesity and have difficulties with blood glucose regulation if the daily carbohydrate intake exceeds 49% of the total caloric content. It has been shown that reducing carbohydrates can optimize the blood glucose regulation and reduce the risk of further weight gain. The risk of weight gain and blood glucose rise is also increased if the diet contains highly saturated and monounsaturated fats. When limiting total calorie content, these subjects can benefit from limiting total carbohydrate intake and changing the fat composition in their diet to monounsaturated fats.

The subject with the genetic mode can react to the body movement and effectively decompose the body fat. In response to exercise, these subjects were able to significantly reduce body weight and most likely maintain the reduced body weight.

Less responsive to carbohydrate restriction and to exercise: subjects with this genetic pattern more readily gain weight gain from excessive carbohydrate intake. They have been able to more successfully lose weight by reducing the amount of carbohydrates in a low calorie diet. Subjects with this genetic pattern are prone to obesity and have difficulties with blood glucose regulation if the daily carbohydrate intake exceeds 49% of the total caloric content. It has been shown that reducing carbohydrates can optimize the blood glucose regulation and reduce the risk of further weight gain. The risk of weight gain and blood glucose rise is also increased if the diet contains highly saturated and monounsaturated fats. When limiting total calorie content, these subjects can benefit from limiting total carbohydrate intake and changing the fat composition in their diet to monounsaturated fats.

5) Fat and carbohydrate balance and react to exercise: subjects with this genetic pattern do not require a continuous low fat or low carbohydrate diet. In these subjects, the major biomarkers, such as body weight, body fat, and blood lipid profile, reacted well to a balanced diet of fat and carbohydrates. Subjects with this genetic pattern, if interested in weight loss, have found that a calorie-restricted balanced diet promotes weight loss and reduces body fat.

6) Fat and carbohydrate balance and are less responsive to exercise: subjects with this genetic pattern do not require a continuous low fat or low carbohydrate diet. In these subjects, the major biomarkers, such as body weight, body fat, and blood lipid profile, reacted well to a balanced diet of fat and carbohydrates. Subjects with this genetic pattern, if interested in weight loss, have found that a calorie-restricted balanced diet promotes weight loss and reduces body fat.

In addition to the recommended nutrition and exercise, the personal treatment/dietary regimen may include a recommended dietary supplement, food supplement, or nutraceutical. "nutraceutical" refers to a functional food that provides other benefits in addition to providing nutrition. Such materials may include health drinks, nutritional drinks (e.g., Slimfast)^TMEtc.) as well as sports herbal drinks and other alcoholic beverages.

Reagent kit

According to some embodiments, provided herein is a kit for detecting a subject's metabolic genotype, the kit comprising reagents (oligonucleotides, salts, enzymes, buffers, etc.) and instructions for using the kit.

According to some embodiments, the kit includes a sample collection tool, including, but not limited to, a swab for collecting saliva; a storage tool for storing collected samples and for transportation. The kit further comprises a CD or CD-ROM, instructions for how to collect the sample, ship the sample, and interpret the genetic information obtained from the sample DNA and convert this information into a treatment/diet or recommended lifestyle. The genotype may be stored, disseminated and displayed via computer networks and the Internet. Treatments/diets and recommended lifestyle include, but are not limited to, those described herein.

Detection of alleles

The constituent alleles are detected using any available technique that can identify allelic, polymorphic, or haploid patterns, including: 1) performing a hybridization reaction between the nucleic acid sample and a probe capable of hybridizing to the allele; 2) sequencing at least a portion of the allele; 3) electrophoretic mobility of the allele or fragment thereof (e.g., a fragment produced by endonuclease digestion) is determined. The allele may optionally be subjected to an amplification step prior to the detection step. Preferred amplification methods are selected from the group consisting of: polymerase Chain Reaction (PCR), Ligase Chain Reaction (LCR), Strand Displacement Amplification (SDA), cloning, and variations of the amplification methods described above (e.g., reverse polymerase chain reaction (RT-PCR), and allele-specific amplification). Oligonucleotides to be amplified can be selected from, for example, metabolic loci that include the side chains of the marker of interest (as required for polymerase chain reaction amplification), or that directly overlap the marker (as in allele-specific oligonucleotide (ASO) hybridization). In a particularly preferred embodiment, the sample is hybridized using a set of primers that hybridize in some cases 5 'and 3' or antisense sequences to the angiopathic-associated allele and are amplified by the polymerase chain reaction.

Alleles can also be detected indirectly, for example, by analysis of the protein product encoded by the DNA. For example, if the marker to be detected is capable of being translated into a mutant protein, the protein can be detected by any protein detection method. These methods include immunoassays and biochemical assays, e.g., fractionation, in which the protein is altered in apparent molecular weight by truncation, elongation, alteration of folding, or post-alteration translational modification.

The aim of designing primers for amplifying specific human chromosomal genomic sequences is that the melting temperature of these primers is at least 50 ℃, wherein the approximate melting temperature can be estimated using the formula Tmelt ═ 2X (# of a or T) +4X (# of G or C).

A number of methods can be used to detect specific alleles at polymorphic sites in humans. Preferred methods for detecting a particular polymorphic allele depend in part on the molecular nature of the polymorphism. For example, the difference in the different allelic forms of the polymorphic sites may be a single base pair of the DNA. This single nucleotide polymorphism (or SNP) is the predominant form of genetic variation, including 80% of all known polymorphisms. Their density in the human genome is estimated to be 1 per 1,000 base pairs on average. Single Nucleotide Polymorphisms (SNPs) are usually biallelic, having only two different forms (although it is theoretically possible that Single Nucleotide Polymorphisms (SNPs) have four different forms, corresponding to four different nucleotide bases in DNA). However, Single Nucleotide Polymorphisms (SNPs) are more stable mutationally than other polymorphisms, which makes them more suitable for linkage disequilibrium association studies between pairs of markers and unknown variants for localizing disease-causing mutations. Furthermore, since Single Nucleotide Polymorphisms (SNPs) typically have only two alleles, they can be detected by simple addition/subtraction without length measurements to determine their genotype, which makes them easier to automate.

There are a variety of methods available for detecting the presence of a particular single nucleotide polymorphism allele in a subject. Advances in this field have provided accurate, simple, and inexpensive large-scale Single Nucleotide Polymorphism (SNP) genotyping methods. Recently, for example, several new technologies have been described, including Dynamic Allele Specific Hybridization (DASH), Microplate Array Diagonal Gel Electrophoresis (MADGE), pyrosequencing, oligonucleotide-specific ligation, TaqMan systems, and various DNA "chip" technologies such as affymetrix snp chips. These methods require amplification of the target gene region, usually by PCR. There are other newly developed methods based on the generation of small signal molecules by invasive cleavage followed by mass spectrometry or immobilized padlock probes and rolling circle amplification, which may eventually lead to the elimination of the need for PCR. Several methods for detecting specific single nucleotide polymorphisms known in the art are summarized below. The process of the present invention is understood to include all available processes.

Several methods have been developed to make it easier to analyze single nucleotide polymorphisms. In one embodiment, single base polymorphisms can be detected using specialized exonuclease resistant nucleotides, as disclosed, for example, in the references of Mundy, c.r. (U.S. patent No. 4,656,127). According to this method, a primer complementary to an allelic sequence immediately 3' to a polymorphic site is hybridized to a target molecule obtained from a particular animal or human. If the polymorphic site on the target molecule contains a nucleotide derivative complementary to the particular exonuclease resistance present, then the derivative will be incorporated at the end of the hybridizing primer. This incorporation makes the primer resistant to exonucleases and therefore detectable. Since exonuclease resistant derivatives of the sample are known, the primers are found to be resistant to exonuclease, which indicates that the nucleotides present at the polymorphic site of the target molecule are complementary to the nucleotides of the nucleotide derivative used in the reaction. The advantage of this method is that it does not require the determination of large amounts of irrelevant sequence data.

In another embodiment of the invention, the nucleotide of the polymorphic site is determined using a solution-based method. See Cohen, D et al (French patent No. 2,650,840; PCT application WO 91/02087). Primers complementary to the allelic sequence immediately 3' to the polymorphic site are used as described by Mundy in U.S. Pat. No. 4,656,127. The method uses a labeled dideoxynucleotide derivative to determine the nucleotide at the site, which if complementary to the nucleotide at the polymorphic site will be incorporated at the end of the primer.

Another alternative is Genetic Bit Analysis or GBA^TMAs described in Goelet, p. et al (PCT application No. 92/15712). The method of Goelet, P. et al uses a mixture of labeled terminators and a primer complementary to a sequence 3' to the polymorphic site. The incorporated labeled terminator is determined by complementarity to the nucleotide present in the polymorphic site of the target molecule to be evaluated. In contrast to the method of Cohen et al (French patent No. 2,650,840; PCT application No. WO91/02087), the method of Goelet, P.et al is preferably a heterogeneous phase assay in which the primers or target molecules are immobilized on a solid phase.

Recently, several primer-directed nucleotide incorporation methods for detecting polymorphic sites in DNA have been described (Komher, J.S.et. al., nucleic acids. Res.17: 7779-7784(1989) (Komher, J.S. et al, 1989, published in "nucleic acids research" No. 17, page 7779-7784), Sokolov, B.P., nucleic acids sRev.18: 3671(1990) (Sokolov, B.P. published in "nucleic acids research" No. 18, page 3671.), (Syvanen, A.C., Genomics 8: 684-692) (Synevan, A.C. et al, 1990 in "Gene-" No. 8, page 692) (published in U.S. Protamura.1147, Nat. S.1147, Nat. S.D.) (Prep. 1. 1147, U.S. 1997, Nat. 1147, USA, No. 11488, USA, No. 1147, USA, No. 10, No. 1147, No. (Prep.),1147, USA, No. 1147, No. 10, No. 1147, USA, No. 1147, USA, No. 11488, USA, No. (SEQ ID No. 10, USA, No. 10, USA, No. 11488, No. (SEQ ID No, T.R. et al, published in 1992 on "hum.Mutat." pp. 159-164 of phase 1); ugozzli, l.et al., GATA 9: 107112(1992) (Ugozzoli, L. et al, 1992, in "GATA" pp. 107-112); nyren, p.et al, anal. biochem.208: 171-. These methods and GBA^TMAll rely on the incorporation of labeled deoxynucleotides to distinguish the bases of the polymorphic sites. In this case, since the signal is proportional to the number of deoxynucleotides incorporated, polymorphisms occurring on the same nucleotide set can result in a signal that is proportional to the length of the set (Syvanen, A. -C., et al., Amer. J. hum. Genet.52: 46-59 (1993)).

For those mutations that cause premature termination of translation of the protein, the Protein Truncation Test (PTT) provides an effective diagnostic method (Roest, et. al., (1993) hum. mol. Genet.2: 1719-21(Roset et al, 1993, 1719-1721, phase 2 of "human molecular genes"; van der Luijt, et. al., (1994) Genomics 20: 1-4(van der Luijt et al, 1994, Genomics, 20, pages 1-4 of "Genomics"). In the protein cut-off detection (PTT) method, RNA is first isolated from available tissue and reverse transcribed, and then the segment of interest is amplified by PCR. Nested PCR amplification is then performed using the reverse transcription PCR product as a template, with primers containing an RNA polymerase promoter and sequences capable of initiating eukaryotic translation. After amplification of the segment of interest, the unique motif incorporated into the primer allows for continued in vitro transcription and translation of the PCR product. The translation products were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the presence of truncated polypeptides indicated the presence of mutations that lead to premature termination of translation. In one variation of this technique, DNA (as opposed to RNA) is used as a PCR template when the target region of interest is from a single exon.

Any cell type or tissue can be used to obtain a nucleic acid sample for use in the diagnostics described herein. In a preferred embodiment, the DNA sample is obtained from a body fluid, for example, blood obtained by known methods (e.g., venipuncture), or saliva. Alternatively, nucleic acid detection can be performed on dry samples (e.g., hair or skin). When RNA or protein is used, cells or tissues that can be used must express the IL-1 gene.

In situ diagnostic methods can also be performed directly on tissue portions (immobilized and/or frozen) obtained from biopsied or excised patient tissue, thereby eliminating the need for nucleic acid purification. Nucleic acid reagents can be used as probes and/or primers in this in situ method (see, e.g., Nuoov, G.J., 1992, PCR in situ hybridization: protocols and applications, Raven Press, NY (Nuoov, G.J., published in 1992, "in situ hybridization PCR: protocols and applications", Raven Press, N.Y.)).

In addition to methods that are primarily used to detect a nucleic acid sequence, profiles can also be evaluated in these detection schemes. The fingerprint profile may be generated, for example, by using differential display methods, Northern analysis and/or RT-PCR.

Preferred detection methods are allele-specific hybridization with probes that overlap with a region of at least one allele of the proinflammatory haplotype of IL-1 and have about 5, 10, 20, 25, or 30 nucleotides around the mutated or polymorphic region. In a preferred embodiment of the invention, several probes capable of specifically hybridizing to other allelic variants involved in osteoporosis are attached to a solid support, such as a "chip" (which can support approximately 250,000 oligonucleotides). Oligonucleotides can be attached to a solid support by a variety of methods, including lithography. These oligonucleotide-containing chips, also called "DNA probe arrays", are used for Mutation detection assays such as, for example, Cronin et al (1996) Human Mutation 7: 244, as described herein. In one embodiment, the chip contains all allelic variants of at least one polymorphic region of a gene. The solid support is then contacted with a detection nucleic acid, which is detected for hybridization to a particular probe. Accordingly, multiple allelic variants of one or more genes can be identified by simple hybridization experiments.

These techniques also comprise a step of amplifying the nucleic acid prior to analysis. Amplification techniques are well known to those skilled in the art and include, but are not limited to, cloning, Polymerase Chain Reaction (PCR), allele-specific polymerase chain reaction (ASA). Ligase Chain Reaction (LCR), nested polymerase chain reaction, autonomous sequence replication (Guatelli, J.C.et. al., 1990, Proc. Natl.Acad.Sci.USA 87: 1874-1878(Guatelli, J.C. et al, published in 1990 "Proc.Acad.USA" 1874. p. 87.)), transcription amplification system (Kwoh, D.Y.et. 1989, Proc. Natl.Acad.Sci.USA 86: 1173-1171177 (Kwoh, D.Y. et. published in 1989 "Acad.USA (USA)" 1173-1177)), and Q-Beberta replicase (Lizardi, P.M.et. et. 1988, Bio/Technology 6: 1197, published in 1986. p. 1198).

The amplification products can be detected in a variety of ways, including length analysis, restriction and then fragment length analysis, detection of specific tagged oligonucleotide primers in the reaction product, Allele Specific Oligonucleotide (ASO) hybridization, allele specific 5' exonuclease detection, sequencing, hybridization, and the like.

Polymerase chain reaction based detection methods involve multiplex amplification of multiple labels simultaneously. For example, it is well known in the art to select PCR primers to produce PCR products that do not overlap in length and that can be analyzed simultaneously. Alternatively, different labels (markers) can be amplified using primers that are labeled differently (labeled) and can be detected separately. Of course, hybridization-based detection methods allow for the detection of multiple PCR products in a sample separately. Other techniques for multiplex analysis of multiple labels are known in the art.

In an exemplary embodiment, which is merely illustrative, the method comprises the steps of: (i) collecting a sample of patient cells, (ii) isolating nucleic acid (e.g., genomic, mRNA, or both) from cells of the sample, (iii) contacting the nucleic acid sample with one or more primers that specifically hybridize to 5 'or 3' of at least one allele of the pro-inflammatory haplotype of IL-1 under conditions in which hybridization and amplification of the allele occurs, and (iv) detecting the amplification product. These detection schemes are particularly useful for detecting nucleic acid molecules that are present in particularly low amounts.

In a preferred embodiment of the patient assay, alleles of the IL-1 proinflammatory haplotype are identified by a change in restriction enzyme pattern. For example, the sample and control DNA are separated, amplified (optionally), digested with one or more restriction enzymes, and the fragment lengths determined by gel electrophoresis.

In another embodiment, the allele can be directly sequenced using any of a variety of sequencing reactions known in the art. Exemplary sequencing reactions include those based on Maxim and Gilbert ((1977) Proc. Natl Acad Sci USA 74: 560) or Sanger (Sanger et al (1977) Proc. Nat. Acad. Sci USA 74: 5463). Any of a variety of automated sequencing methods can be used when performing patient assays (see, e.g., Biotechnicques (1995) 19: 448), including sequencing by mass spectrometry (see, e.g., PCT publication WO 94/16101; Cohen et al (1996) Adv Chromatogr 36: 127-. In particular embodiments, it is only one, two or three occurrences of nucleic acid bases that need to be determined in the sequencing reaction. For example, an A-track or the like may be performed, for example, in which only one nucleic acid is detected.

In another embodiment, protection from the action of cleaving reagents such as nucleases, hydroxylamine or osmium tetroxide and piperidine can be used to detect mismatched bases in RNA/RNA or RNA/DNA or DNA/DNA heteroduplexes (Myers, et al (1985) Science 230: 1242(Myers et al, published in 1985 at "Science" p. 230 1242)). In general, "mismatch cleavage" techniques first provide a heteroduplex formed by hybridizing (labeled) RNA or DNA containing the wild-type allele to a sample. The double-stranded duplexes are treated with a reagent that cleaves the single-stranded region of the duplex, which exists, for example, due to a base pair mismatch between the control and sample strands. For example, the RNA/DNA duplex can be treated with RNase and the DNA/DNA hybrid treated with S1 nuclease to digest mismatched regions. In other embodiments, DNA/DNA or RNA/DNA duplexes may be treated with hydroxylamine or osmium tetroxide and piperidine to digest mismatched regions. After the mismatch region was digested, the resulting material was separated according to length on denaturing polyacrylamide gel to determine the site of mutation. See, e.g., Cotton et al (1988) Proc. Natl Acad Sci USA 85: 4397(Cotton et al, 1988, at 4397, 85 th of Proc. Natl. Acad. Sci. USA); and Saleeba et al (1992) Methods enzymol.217: 286 ℃ 295(Saleeba et al published in 1992 on "methods in enzymology" at stage 217, pages 286 ℃ 295). In a preferred embodiment, the control DNA or RNA may be labeled for detection.

In yet another embodiment, the mismatch cleavage reaction uses one or more proteins that recognize mismatched base pairs of double-stranded DNA (so-called "DNA mismatch repair" enzymes). For example, the mutY enzyme of E.coli cleaves G/A mismatched A and the thymine DNA glycosylase of HeLa cells cleaves G/T mismatched T (Hsu et al (1994) Cardigenesis 15: 1657-1662). According to an exemplary embodiment, probes based on alleles of haplotypes of the IL-1 locus hybridize to cDNA or other DNA products of the test cell. The duplexes are treated with a DNA mismatch repair enzyme and the cleavage products, if any, can be detected by electrophoresis or the like. See, for example, U.S. Pat. No. 5,459,039.

In other embodiments, the IL-1 locus allele can be identified using a change in electrophoretic mobility. For example, single-stranded conformational polymorphisms (SSCP) can be used to detect differences in electrophoretic mobility between mutant and wild-type nucleic acids (Orita et al (1989) Proc Natl.Acad.Sci USA 86: 2766(Orita et al, 1989, journal of the national academy of sciences USA, 86, p.2766), see also Cotton (1993) Mutat Res 285: 125-144(Cotton, 1993, mutation research, p.125-144), and Hayashi (1992) Genet Anal Tech Appl 9: 73-79(Hayashi, 1992, gene analysis techniques application, p.9, p.73-79)). The single-stranded DNA fragments of the sample and control IL-1 locus alleles are denatured and can be renatured. The secondary structure of a single-stranded nucleic acid differs depending on the sequence, and the resulting change in electrophoretic mobility can be detected even by a single base. The DNA fragments may be labeled or may be detected with a labeled probe. The sensitivity of the assay can be increased with RNA (rather than DNA), where secondary structure is more sensitive to sequence changes. In a preferred embodiment, the bulk method uses heteroduplex analysis to separate double-stranded heteroduplex molecules based on changes in electrophoretic mobility (Keen et al (1991) Trends Genet 7: 5).

In yet another embodiment, movement of the allele on a polyacrylamide gel containing a gradient of denaturant is detected by Denaturing Gradient Gel Electrophoresis (DGGE) (Myers et al (1985) Nature 313: 495). When Denaturing Gradient Gel Electrophoresis (DGGE) is used as the analytical method, the DNA is modified to ensure that it is not completely denatured, for example by adding a GC clamp of about 40bp of high melting GC-rich DNA by PCR. In another embodiment, a temperature gradient is used instead of a denaturing reagent gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265: 12753).

Examples of other methods for detecting alleles include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, an oligonucleotide primer in which a known mutation or nucleotide difference (e.g., allelic variant) is located at the center can be prepared and then hybridized with a target DNA under conditions in which hybridization occurs only in the presence of perfect pairing (Saiki et al (1986) Nature 324: 163) (Saiki et al, 1986, pp. 163, Nature 324); saikiet al (1989) Proc. Natl Acad. Sci USA 86: 6230(Saiki et al, 1989, journal of the national academy of sciences USA, 86, 6230). Such allele-specific oligonucleotide hybridization techniques can be used to detect one mutation or polymorphic region in each reaction, wherein the oligonucleotide hybridizes to the target DNA amplified by PCR or to a plurality of different mutation or polymorphic regions when the oligonucleotide is attached to a hybridization membrane and hybridized to labeled target DNA.

Alternatively, allele-specific amplification techniques that rely on selective PCR amplification may be used in conjunction with the present invention. Oligonucleotides used as primers for specific amplification can be either in the center of the molecule (to make amplification dependent on differential hybridization) (Gibbs et al (1989) Nucleic Acids Res.17: 2437-2448(Gibbs et al, published in 1989 at "Nucleic Acids research" No. 17, 2437-2448)), or at the 3' end of a primer that under appropriate conditions can prevent mismatches or reduce polymerase extension (Prossner (1993) Tibtech 11: 238), carrying a mutated or polymorphic region of interest. In addition, new restriction sites can be introduced into the mutated region for cleavage-based detection (Gasparini et al (1992) mol. cell Probes 6: 1). In particular embodiments, amplification may also be performed using Taq ligase (Barany (1991) Proc. Natl. Acad. Sci USA 88: 189). In this case, ligation occurs only if the 3 'ends of the 5' sequences are perfectly matched, which allows the presence of a known mutation at a particular site to be detected by checking for the presence of amplification.

In another embodiment, allelic variants are identified using Oligonucleotide Ligation Assay (OLA), as described in U.S. Pat. No. 4,998,617 and Landegren, U.T. (1988) Science 241: 1077-1080(Landegren, U.S. Pat. No. 241 and 1988, published at 1077-1080 of "Science" 241). The OLA method uses two oligonucleotides that hybridize to adjacent sequences on a single strand of the target. One of the oligonucleotides is linked to a separation label, for example a biotinylated label, and the other is detectably labeled. If the exact complementary sequence is found in the target molecule, the oligonucleotides will hybridize such that their ends are adjacent, creating a ligation substrate. The linkage allows recovery of the labeled oligonucleotide with avidin, or another biotin ligand. Nickerson, D.A. et al, describe a nucleic acid detection method that combines the properties of PCR and OLA (Nickerson, D.A.et al, (1990) Proc. Natl. Acad. Sci. USA 87: 8923-27 (a reference published by Nickerson, D.A. et al in 1990, proceedings of the national academy of sciences USA 8923-8927). In this method, exponential amplification of target DNA is achieved by PCR, followed by detection by OLA.

Several techniques based on this OLA method have been developed which can be used to detect haploidy alleles of the IL-1 locus. For example, U.S. Pat. No. 5,593,826 discloses an OLA that forms conjugates having phosphoramidate linkages using oligonucleotides having 3 'amino groups and 5' phosphorylated oligonucleotides. In another variation of OLA described by Tobe et al ((1996) Nucleic Acids Res 24: 3728), OLA in combination with PCR allows typing of both alleles in a single microtiter well. By labeling each allele-specific primer with a unique hapten, i.e., digoxigenin and fluorescein, each OLA reaction can be detected by labeling the hapten-specific antibody with a different enzyme reporter, alkaline phosphatase or horseradish peroxidase. This system allows the detection of two alleles in a high throughput format that produces two different colors.

In another aspect, the invention features a kit capable of performing the above-described assay. According to some embodiments, the kits of the invention may include means for determining the genotype of a subject based on one or more metabolic genes. The kit further comprises nucleic acid sample collection means. The kit also includes a control sample, which may be either a positive or negative control, or a standard, and/or a computing instrument for evaluating the results and an additional reagent and component, including: DNA amplification reagents, DNA polymerases, nucleic acid amplification reagents, restriction enzymes, buffers, nucleic acid sampling equipment, DNA amplification equipment, deoxynucleosides, oligonucleotides (e.g., probes and primers), and the like.

For use in a kit, the oligonucleotide may be any of a variety of natural and/or synthetic compositions such as synthetic oligonucleotides, restriction fragments, cDNAs, synthetic Peptide Nucleic Acids (PNAs), and the like. The detection kit and method may also use labeled oligonucleotides to facilitate detection identification. Examples of useful labels include radioactive labels, enzymes, fluorescent compounds, streptavidin, avidin, biotin, magnetic components, metal binding components, antigen or antibody components, and the like.

As described above, the reference may be a positive reference or a negative reference. Further, the reference sample may include a positive (or negative) product of the allele detection technique used. For example, where the allele detection technique is PCR amplification followed by size fractionation, the resulting reference sample may comprise DNA fragments of appropriate size. Allele detection techniques include the detection of mutant proteins, and similarly, reference samples may include samples of mutant proteins. However, it is preferred that the reference sample comprises the material to be detected. For example, the reference may be a genomic DNA sample or a cloned portion of a metabolic gene. Preferably, however, the reference sample is a highly purified sample of genomic DNA, wherein the sample to be tested is genomic DNA.

The oligonucleotides present in the kit can be used to amplify a region of interest or to direct the hybridization of an allele-specific oligonucleotide (ASO) to a marker to be detected. Thus, the oligonucleotide may flank the marker of interest (as required for PCR amplification) or directly overlap the marker (as in allele-specific oligonucleotide (ASO) hybridization).

The information obtained using the assays and kits described herein (used alone or in combination with other genetic defect or environmental factor information) can be useful in determining whether a subject who does not exhibit any symptoms has or is likely to develop a particular disease or condition. In addition, such information can provide a more specific way to prevent the occurrence or worsening of the disease or condition. For example, this information enables physicians to more effectively prescribe a treatment to address the molecular basis of the disease or condition.

Optionally, the kit may further comprise a DNA sampling means. DNA sampling tools are well known to those of ordinary skill in the art and include, but are not limited to, substrates such as filter paper, AmpliCard^TM(university of Sheffield, England S1O 2 JF; Tarlow, J W, et al, J.of invest.Dermatol.103: 387-; DNA purification reagents, e.g. Nucleon^TMKits, lysis buffers, protease solutions, and the like; PCR reagents such as 10X reaction buffer, constant temperature polymerase, dNTP, etc.; and allele detection tools such as Hinfl restriction enzyme, allele specific oligonucleotides, denatured oligonucleotide primers for nested polymerase chain reaction from dried blood.

Another embodiment of the invention relates to kits for detecting a predisposition to respond to certain dietary and/or exercise levels. Such kits may include one or more oligonucleotides, including 5 'and 3' oligonucleotides, which 5 'and 3' oligonucleotides hybridize at the 5 'or 3' site to at least one metabolic gene site or haploid allele. The polymerase chain reaction amplified oligonucleotide may be partially hybridized between 25 and 2500, preferably between about 100 and about 500 base moieties, to produce a polymerase chain reaction product of suitable size to facilitate subsequent analytical testing.

Table 5: particularly preferred primers for use in the diagnostic method of the invention are shown in the following table:

by utilizing the latest sequence information obtained from the human chromosome 4q28-q31 including the human fatty acid binding protein 2(FABP2) site and the latest human polymorphism information obtained from the site, it is possible to more conveniently design additional oligonucleotides for use in amplification and detection of metabolic gene polymorphism alleles according to the method of the present invention. Using this sequence information and standard techniques known in the art for designing and optimizing primer sequences, appropriate primers for detecting human polymorphisms in metabolic genes can be readily designed. For example, by using commercially available Primer selection programs, such as Primer 2.1, Primer 3 or GeneFisher (see, Nicklin M.H.J., Weith A.Duff G.W., "A Physical Map of the Region of the Human Interleukin-1. alpha., Interleukin-1. beta., and Interleukin-1Receptor Antagonist Genes" Genomics 19: 382(1995) (Nicklin M.H.J., Weith A.Duff G.W., 1995 at "Gene" No. 19, page 382 "Physical Map of the Region of the Interleukin-1. alpha., Interleukin-1. beta., and Interleukin-1Receptor Antagonist Genes" Nothing H.G., intussuming "of Molecular control protein 1. beta. and Interleukin-1Receptor Antagonist Genes" at "Gene" No. 19, 23, PAC.41 "of the sequence of the Human Interleukin-1. alpha.," Interleukin-1. beta. and Interleukin-1Receptor Antagonist Genes "at" PAC.1997, PAC.41: PAC.1. PAC.1997, PAC.41, PAC.1. PAC.1997, and PAC.370. 1. C.1. C. -1 molecular cloning of the Gene Cluster: the construction of the complete YAC/PAC conformation and partial translation map of the chromosome 2q13 region "; clark, et al (1986) nucleic acids res, 14: 7897-.

In another aspect, the invention features a kit for performing the above assay. According to some embodiments, the kit of the invention may comprise means for determining the genotype of a subject based on one or more metabolic genes. The kit may further comprise nucleic acid sampling means. The kit may also include a positive or negative reference sample and/or known computing device for evaluating the results obtained, and may also include other reagents and components including: DNA amplification reagents, DNA polymerase, nucleic acid amplification reagents, restriction enzymes, buffers, nucleic acid sampling devices, DNA purification devices, deoxynucleotides, oligonucleotides (e.g., probes and primers, etc.).

For use in a kit, the oligonucleotide can be any natural and/or synthetic composition, e.g., a synthetic oligonucleotide, a restriction fragment, a cDNA, a synthetic Peptide Nucleic Acid (PNA), and the like. The test kits and methods may also use labeled oligonucleotides to allow easier identification of the test. Examples of labels that may be used include radiolabels, enzymes, fluorescent compounds, streptavidin, avidin, biotin, magnetic groups, metal binding groups, antigens or antigenic groups, and the like.

As described above, the reference may be a positive reference or a negative reference. Further, the reference sample may comprise a positive (or negative) product of the allele detection technique used herein. For example, where the allele detection technique is PCR amplification followed by size fractionation, the resulting reference sample may comprise DNA fragments of appropriate size. Allele detection techniques include the detection of mutant proteins, and similarly, reference samples may include samples of mutant proteins. However, it is preferred that the reference sample comprises the material to be detected. For example, the reference may be a genomic DNA sample or a cloned portion of a metabolic gene. Preferably, however, the reference sample is a highly purified sample of genomic DNA, wherein the sample to be tested is genomic DNA.

The information obtained using the assays and kits described herein (used alone or in combination with other genetic defects or environmental factor information that promote the development of arthritis) can be useful in determining whether a subject who does not exhibit any symptoms has or is likely to develop a particular disease or condition. In addition, such information can provide a more specific way to prevent the occurrence or worsening of the disease or condition. For example, this information enables physicians to more effectively prescribe a treatment to address the molecular basis of the disease or condition.

The kit, optionally, may further comprise a DNA sampling means. DNA sampling tools are well known to those skilled in the art and include, but are not limited to, substrates such as filter paper, AmpliCard^TM(university of Sheffield, England SlO 2 JF; Tarlow, J W, et al, J.of invest. Dermatol.103: 387-389(1994) (Tarlow J.W et al, 1994 at "J.of invest. Dermatol" at page 103 387-389)) and the like; DNA purification reagents such as Nucleon^TMA kit, a dissolution reagent, a protease solution, and the like; PCR reagents such as 10 × reaction buffer, thermostable polymerase, dNTPs, etc.; and allele detection means such as HinfI restriction enzyme, allele-specific oligonucleotides, degenerate oligonucleotide primers for nested PCR of dried blood.

Definition of

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, suitable materials and methods are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the definitions of the claims.

For the purposes of promoting an understanding of the embodiments described herein, references are made to preferred embodiments and specific language is used to describe the preferred embodiments. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. As used in this disclosure, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes plural and singular compositions, "a therapeutic agent" refers to one or more therapeutic agents and/or pharmaceutical agents and equivalents thereof known to those skilled in the art to which the invention pertains, and so forth.

The term "allele" refers to different sequence variants found on different polymorphic regions. The sequence variants may be single base variations or multiple base variations, including but not limited to insertions, deletions, or substitutions, or may be a variable number of sequence repeats.

The term "allelic manner" refers to the identity of an allele or alleles at one or more polymorphic regions. For example, the allelic pattern may consist of a single allele of a polymorphic site, such as peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282) allele 1. Alternatively, the allelic mode may consist of a single homozygote binding state or a heterozygote state at a single polymorphic site. For example, the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282) allele 2.2 is an allelic version in which there are two second allelic copies and a state of isotype binding equivalent to the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl801282) allele 2. Alternatively, the allelic pattern may consist of the identity of alleles at more than one polymorphic site.

The term "reference" or "reference sample" refers to any sample suitable for the detection method used. The reference sample may contain the product of the allele detection technique used or the substance to be detected. Further, the reference may be a positive reference or a negative reference. By way of example, the allele detection technique is PCR amplification followed by size fractionation, and the resulting reference sample may include DNA fragments of appropriate size. Allele detection techniques include the detection of mutant proteins, and similarly, reference samples may include samples of mutant proteins. However, it is preferred that the reference sample comprises the material to be detected. For example, the reference may be a genomic DNA sample or a cloned portion of a metabolic gene. Preferably, however, the reference sample is a highly purified sample of genomic DNA, wherein the sample to be tested is genomic DNA.

The terms "disruption of a gene" and "targeted disruption" or any similar phrase refer to site-specific blocking of a native DNA sequence as compared to a wild-type copy of the gene to prevent expression of the gene in a cell. The block may be formed by gene deletion, insertion or alteration, or any combination thereof.

The term "haplotype" as used herein means at a statistically significant level (P)_corr< 0.05) a set of alleles inherited together as a cohort (linkage disequilibrium). The phrase "metabolic haplotype" as used herein refers to the haplotype of the metabolic gene locus.

By "increased risk" is meant a statistically higher frequency of occurrence of a disease or condition in individuals carrying a particular polymorphic allele as compared to the frequency of occurrence of the disease or condition in members of the population not carrying the particular polymorphic allele.

The term "isolated" as used herein with respect to a nucleic acid, such as DNA or RNA, refers to a molecule that is separated from other DNA, or RNA, respectively, that is present in a macromolecule of natural origin. The term isolated as used herein also refers to nucleic acids or peptides that are substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, and substantially free of chemical precursors or other chemicals when chemically synthesized. Furthermore, "isolated nucleic acid" includes nucleic acid fragments that do not occur naturally as fragments and do not occur in the natural state. The term "isolated" as used herein also refers to polypeptides isolated from other cellular proteins, including purified and recombinant polypeptides.

"linkage disequilibrium" refers to the co-inheritance of two alleles at a higher frequency than would be expected from the individual frequencies of occurrence of each allele in a given control population. The expected frequency of occurrence of the two alleles inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur with the expected frequency are referred to as "linkage disequilibrium". The reason for linkage disequilibrium is often unclear. Possibly due to the selection of specific combinations of alleles or a recent mixture of genetically heterogeneous populations. Furthermore, in the case where the marker is closely associated with a disease gene, if a disease mutation has recently occurred, the allele (or linked group of alleles) is expected to be associated with the disease gene, and therefore there is insufficient time for equilibrium to be achieved by recombination events on a particular chromosomal region. When it refers to an allelic mode consisting of more than one allele, the first allelic mode is in linkage disequilibrium with the second allelic mode if all alleles comprising the first allelic mode are in linkage disequilibrium with at least one allele of the second allelic mode.

The term "marker" refers to a sequence located in the genome that is known to vary between different subjects.

"mutant gene" or "mutation" or "functional mutation" refers to an allelic form of a gene that alters the phenotype of a patient having a mutant gene relative to a patient without the mutant gene. The phenotypic change caused by the mutation may be corrected or compensated for by a particular agent. A mutation is said to be recessive if the patient must be homozygous for the mutation in order to have an altered phenotype. The mutation is said to be dominant if one copy of the mutant gene is sufficient to alter the phenotype of the patient. A mutation is said to be co-dominant if the patient has one copy of the mutant gene and has a phenotype that is intermediate between that of a homozygous patient and a heterozygous patient (for the gene).

The term "nucleic acid" as used herein refers to a polynucleotide or oligonucleotide, e.g., deoxyribonucleic acid (DNA), and, if appropriate, ribonucleic acid (RNA). The term is also to be understood as encompassing equivalents or analogs of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) prepared from nucleotide analogs (e.g., peptide nucleic acids), as well as single-stranded (sense or antisense) or double-stranded polynucleotides useful in the embodiments described herein.

The term "polymorphism" refers to the co-existence of more than one form of a gene or portion thereof (e.g., allelic variant). A portion of a gene having at least two different forms, i.e., two different nucleotide sequences, is referred to as "a polymorphic region of the gene". The specific gene sequence located at a polymorphic region of a gene is an allele. The polymorphic region may be a single nucleotide, differing in different alleles. Polymorphic regions may also be several nucleotides long.

The term "predisposition to a disease," also called "predisposition" or "susceptibility" to a disease or any similar phrase, refers to the association of a particular allele found herein with a patient developing a particular disease (e.g., vascular disease) or the prediction of whether a patient is developing a particular disease. The allele is over-represented in frequency in individuals with the disease as compared to healthy individuals. Thus, these alleles can be used to predict disease even in presymptomatic or pre-diseased individuals.

The term "specifically hybridize" or "specifically detect" as used herein refers to the ability of a nucleic acid molecule to hybridize to at least about 6 contiguous nucleotides of a sample nucleic acid.

"transcriptional regulatory sequence" is a general term used throughout this specification to refer to DNA sequences, such as initiation signal sequences, enhancers, and promoters, that are capable of inducing or controlling the transcription of a protein coding sequence to which the DNA sequence is operably linked.

The term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of preferred vector is an episome, i.e., a nucleic acid that is capable of replication extrachromosomally. Preferred vectors are those capable of autonomous replication and/or expression of the nucleic acid to which they are linked. Vectors capable of directly expressing a gene to which they are operably linked are referred to herein as "expression vectors". Generally, expression vectors for recombinant DNA technology are in the form of "plasmids", which generally refer to circular double-stranded DNA loops that are not chromosomally associated when in vector form. In the present specification, "plasmid" and "vector" are used interchangeably as the plasmid is the most commonly used form of vector. However, the invention also includes other forms of expression vectors which serve equivalent functions and which later become known in the art.

The term "wild-type allele" refers to an allele of a gene that results in a wild-type phenotype when two copies of the allele are present in a patient. Since a particular nucleotide change in a gene may not affect the phenotype of a patient having two copies of the nucleotide changed gene, a particular gene may have several different wild-type alleles.

The following examples are illustrative only and are not intended to limit the methods and compositions of the present invention. Other suitable modifications and adaptations of the various conditions and parameters normally used in therapy, and other modifications and adaptations apparent to those of ordinary skill in the art, are also included within the spirit and scope of the embodiments of the invention.

Example 1

Performing clinical studies to identify the relationship between genes and changes in metabolic effects associated with weight management; establishing acceptance criteria to determine which genetic variations affect metabolic pathways that can be modulated by changing diet and lifestyle; determining genotypes that have been shown to have increased risk and suggesting a genotype that can be risk-modulated by diet or lifestyle intervention; and, combining evidence, test result interpretation, diet/lifestyle intervention and benefit/risk analysis that can support test structure selection, and combining the above clinical study results, a weight management test can be developed.

The gene/polymorphism selection criteria require the following evidence: polymorphisms have an important relationship with weight management phenotypes (e.g., body weight, body fat, body mass index) as shown by three or more independent similar studies showing the same genotype relationships; the gene has plausible biological effects in weight management; the polymorphism is associated with a functional effect on the molecular genetic level or is determined by biomarkers known to affect body weight and/or health outcome; and, as can be seen from similar studies of specific recommended species resulting from two or more mutually independent polymorphic genotypes, the intervention response has shown differences between genotypes.

Scientific rationality of test groups

The scientific principles of these experiments are based on a broad summary of all scientific literature prior to 4 months of 2007. The evidence disclosed herein was evaluated in terms of a prospective representation of accepted criteria. These evidences were collated by the hierarchy of gene > polymorphism > complex genotype to define and adjust the interpretation of the test results for the test panel.

The evaluation process comprises the following steps:

1. the subject genes are identified by identifying important relationships between metabolic pathways and body weight homeostasis.

2. Acceptance criteria were established to determine which genetic variations could affect metabolic pathways in a particular way that could be effective in improving metabolic pathways by improving diet and exercise patterns. These include the following evidence:

a) polymorphisms have an important relationship with a corresponding phenotype (e.g., body weight, body fat, body mass index) as shown by three or more similar studies that are independent of each other, which show the same genotype-phenotype relationship.

b) The gene has plausible biological effects in weight management.

c) The polymorphism is associated with a functional effect on the DNA level or is determined by biomarkers known to affect body weight and/or health outcomes.

d) The subject's response to an intervention, such as a dietary intervention or a motor intervention, may be stratified by genotype. This evidence must exist independently of more than two.

3. A comprehensive scientific literature search was conducted to evaluate the impact of genetic variation on several aspects: a) physicochemical processes of metabolism; b) obesity/weight management and health status relationships, and c) response to intervention when modulated by changes in body weight or obesity or biomarker changes.

4. The genotype that has been shown to make a subject more prone to weight gain is determined and the weight gain can be altered by specific diet or exercise strategies.

5. Evidence that can support test structure selection, test result interpretation, diet/lifestyle intervention, and benefit/risk analysis is compiled.

The following genes meet the criteria outlined above. They have been screened to determine their effect on different pathways affecting body weight, genes associated with increased risk of developing obesity. These genes were chosen because they can be used to genotype a subject's response to the effects of weight management intervention. These genes are: fatty acid binding protein 2(FABP 2); peroxidase proliferation factor activated receptor-gamma (PPARG); beta-2adrenergic receptor (ADRB 2); and adrenergic beta-3 receptor (ADRB 3).

Theory of complex genotypes

After identifying genes/polymorphisms that meet or exceed the predicted development criteria contained in this panel, combinations thereof are analyzed to determine whether all of the composite genotypes encountered by all 5 polymorphisms can be divided into distinct species and support a particular experimental interpretation. Results were divided into three categories (response to fat limitation, response to carbohydrate limitation, and fat and carbohydrate balance) based on evidence of the subjects' response to dietary macronutrients. The results can also be divided into two different categories (reacting to motion or reacting less to motion) based on evidence of the subject's response to motion. The resulting class model or genotype for three by two (6 units) is shown in table 7.

Responsive to a fat-restricted diet

This category consists of people carrying the following complex genotypes: fatty acid binding protein 2(FABP2) alanine 54 threonine and the peroxidase proliferation factor activated receptor-gamma (PPARG) proline 12 alanine. Subjects carrying the peroxidase proliferation factor activated receptor-gamma (PPARG)12 proline/proline genotype also carry the fatty acid binding protein 2(FABP2) threonine 54allele, and such subjects also belong to this category. In weight management, such subjects have difficulty losing weight if the specific fat intake is not limited. The fatty acid binding protein 2(FABP2) threonine 54 variant has more than two times stronger binding affinity for long chain fatty (1) acids and therefore has greater fat absorption and/or the process of dietary fatty acid handling through the gut (2). The threonine 54 variant is capable of increasing the process of absorption and/or processing of dietary fatty acids through the intestinal tract. The peroxidase proliferation factor activated receptor-gamma (PPARG) plays an important role in adipocyte formation (fat storage) and lipid metabolism (fat migration). The peroxidase proliferation factor activated receptor-gamma (PPARG) is a receptor located in the nucleus of the adipocyte. When activated by dietary fat, the peroxidase proliferation factor-activated receptor-gamma (PPARG) receptor binds to specific DNA sequences that, in turn, "turn on" certain genes that promote storage of dietary fat in adipocytes. In humans, enhanced peroxidase proliferation factor activated receptor-gamma (PPARG) activity is associated with increased obesity. Alanine 2 variants are associated with a reduced peroxidase proliferative factor activated receptor-gamma (PPARG) activity (43, 44). People carrying 12 proline/proline are more likely to respond to the amount of fat in the diet than people carrying 12 alanine. In response to the intervention, the person carrying alanine 12 has greater metabolic flexibility in storing and moving fat. Thus, subjects carrying 12 proline/proline are able to accumulate fat from the diet more efficiently. Humans carrying the 12 proline/proline genotype have increased binding affinity of the peroxidase proliferation factor activated receptor-gamma (PPARG) to DNA compared to humans carrying alanine 12, which in turn results in a more potent receptor activation, thereby promoting fat storage.

Responsive to carbohydrate limitation

Such species include humans carrying different combinations of genes as follows: peroxidase proliferation factor activated receptors-gamma (PPARG) proline 12 alanine and beta-2adrenergic receptor (ADRB2) glutamine 27glutamic acid (Gln27 Glu). Persons carrying the peroxidase proliferation factor activated receptor-gamma (PPARG)12 alanine/' genotype (alanine allele carrier) and/or carrying the beta-2adrenergic receptor (ADRB2) glutamate 27 allele have difficulty in weight management unless their dietary carbohydrate intake is restricted. In two separate studies, each of which was conducted on only one of the two genes/Single Nucleotide Polymorphisms (SNPs), researchers found that subjects carrying this variant allele had a reduced propensity to gain weight/develop obesity when carbohydrate intake was limited to less than 50% of the total calories, as compared to persons carrying the same genotype but with more than 50% (30, 38) of the total calories. This suggests that one of these changes is a difference in the risk of developing diabetes under carbohydrate-limiting conditions. In addition, one of these studies showed that subjects with the variant allele had a reduced risk of insulin resistance when their carbohydrate intake was less than 50% of the total calories (30). Intervention in subjects carrying alanine 12 demonstrated that subjects carrying alanine 12 had more weight loss (18) and greater improvement in insulin sensitivity as a response to low calorie diet (19) and exercise training (45-47) than subjects carrying no gene. This result can be explained by the reduced peroxidase proliferator activated receptor- γ (PPARG) activity associated with the alanine 12 variant, which results in a reduced potent stimulatory effect of the peroxidase proliferator activated receptor- γ (PPARG) targeted gene, less susceptibility to obesity (reduced capacity to store fat), and thus greater insulin sensitivity. It is reasonable to recommend a carbohydrate-restricted diet for subjects carrying either the alanine 12 or glutamate 27 allele, because such a diet is one with an increased risk of obesity for high carbohydrate diets, and this genotype together with dietary/exercise intervention is associated with an improvement in insulin sensitivity.

Intervention studies using changes in body weight and insulin sensitivity have shown to be potent for the peroxidase proliferation factor activated receptor-gamma (PPARG)12 alanine/, and beta-2adrenergic receptor (ADRB2)27 glutamate (27 Glu)/(18, 30, 38, 45-47). However, no study was conducted to evaluate the role of these two polymorphisms in one population. Thus, it is more appropriate to incorporate a peroxisome proliferator activated receptor- γ (PPARG)12 alanine/, and/or "β -2adrenergic receptor (ADRB2)27 glutamic acid (27Glu)/, genotype host in this manner than would be required to combine two Single Nucleotide Polymorphism (SNP) genotypes.

The only contradiction that exists among the five Single Nucleotide Polymorphism (SNP) genotypes is that when a subject carrying the β -2adrenergic receptor (ADRB2) glutamate 27 carries a combination of both the peroxidase proliferation factor activated receptor- γ (PPARG)12 proline/proline and fatty acid binding protein 2(FABP2)54 threonine/, it would make the subject more suitable to be classified as a "responding to fat-restricted diet". The way in which this test assigns the subject to "respond to a fat-restricted diet" is based on scientific evidence that the peroxidase proliferation factor activated receptor-gamma (PPARG) and fatty acid binding protein 2(FABP2) polymorphisms have significant advantages in gene-diet interactions with body weight, and/or that the body fat-associated phenotype (1, 2, 9, 10, 16, 18) is more dominant than the body's gene-diet interaction with the beta-2adrenergic receptor (ADRB2) for carbohydrate regulation (21, 30, 31).

Many studies have demonstrated that subjects carrying the threonine 54allele of fatty acid binding protein 2(FABP2) are at risk for metabolic syndrome (48-50). Other studies have also shown that risk factors associated with glucose metabolism (insulin, blood glucose, triglycerides) can be improved by reducing the amount of saturated fat intake. In most cases, intervention studies on the type of fat in the diet include appropriate amounts of dietary carbohydrates. Studies that do not directly relate to the genotype of fatty acid binding protein 2(FABP2) have shown that insulin levels and glycemic control can be improved by modulating carbohydrate intake (51-53). Rather than concentrating on reducing dietary fat, subjects carrying the peroxidase proliferation factor activated receptor-gamma (PPARG) 12/alanine/, and fatty acid binding protein 2(FABP2)54 threonine/, complex genotype are more likely to benefit from reducing their carbohydrate intake.

Less reaction to motion

Persons carrying a particular genotype, for example, either the adrenergic beta-3 receptor (ADRB3) gene or the beta-2adrenergic receptor (ADRB2) gene, have a genetic predisposition that makes them less responsive to exercise as a strategy for weight control. Both of these polymorphisms play an important role in the removal of fat from adipose tissue (lipolysis) by modulating the response to catecholamines. The β -2adrenergic receptor (ADRB2) glycine 16 variant (even when combined with the glutamate 27 variant in vitro experiments) was associated with decreased adrenergic receptor responsiveness (21). These two polymorphisms are in close linkage disequilibrium. Thus, detection of the glycine 16 variant also identified a majority of variants carrying glutamate 27, which glutamate 27 variants are also associated with the same predisposition. Adrenergic beta-3 receptor (ADRB3) arginine 64 variants are associated with reduced receptor function and reduced lipolysis. During exercise, subjects carrying this variant are likely to show reduced lipolysis, thus reducing the ability to burn fat, as a response to exercise, which in turn results in less weight loss. Many intervention studies have consistently demonstrated that people carrying the arginine 64 variant are more difficult to lose weight in response to diet/exercise than non-carriers. Subjects carrying the beta-2adrenergic receptor (ADRB2) glycine 16 are less likely to lose weight by exercise than non-carriers (23), or subjects carrying the beta-2adrenergic receptor (ADRB2) glycine 16 are less likely to lose weight by a combination of diet and exercise than non-carriers (28). Considering that during exercise, both adrenergic receptors affect the response to catecholamines and that the β -2adrenergic receptor (ADRB2) glycine 16 and adrenergic β -3 receptor (ADRB3) arginine 64 have reduced receptor function, subjects carrying any of the above polymorphisms should also be considered to be included in a complex format that is less responsive to exercise.

Results were divided into three separate categories based on evidence of response to dietary macronutrients and into two different categories based on evidence of response to exercise. The three-by-two species or genotype patterns obtained are shown below (Table 6).

Table 6: composite genotype risk profile

Note that: the percentage in each composite genotype category represents the expected occurrence of this genotype in Caucasian in Quebec family research (QFS).

Within these groups, we name these polymorphisms based on amino acid changes in the protein due to nucleotide changes in the DNA (e.g., "54 threonine" refers to a nucleotide change in the DNA that results in the substitution of threonine for amino acid 54 of the amino acid sequence of the fatty acid binding protein 2(FABP2) protein). Asterisks indicate the alleles that may be present (e.g., "54 threonine/art" means that the second allele may be alanine or threonine).

Composite genotype pattern # 1-response to fat and carbohydrate balanced diet, response to exercise: a subject carrying a complex genotype of fatty acid binding protein 2(FABP2) rsl799883, 1.1 or G/G (54 alanine/alanine), peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282, 1.1 or C/C (12 proline/proline), and β -2adrenergic receptor (ADRB2) rslO42714, 1.1 or C/C (27 glutamine/glutamine), and β -2adrenergic receptor (ADRB2) rslO42713, 2.2 or a/a (16 arginine/arginine), and adrenergic β -3 receptor (ADRB3) rs4994, 1.1 or T/T (64 tryptophan/tryptophan). This category includes subject genotypes known to be responsive to low-fat or low-carbohydrate, calorie-restricted diets, exhibiting weight variation. From the variants tested in the panel, these subjects did not show a consistent genetic trend towards injury when classified as fat in restricted diets or carbohydrate in restricted diets. They showed normal energy metabolism response to regular exercise, thereby achieving their weight management goals. These complex genotypes were present in caucasian humans at a rate of 2%.

Composite genotype pattern # 2-responds to fat restriction, to exercise: a body carrying a complex of fatty acid binding protein 2(FABP2) rsl799883, 2.2 or 1.2(a/a or G/a) (54 threonine /) and peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282, 1.1 or C/C (12 proline/proline) and β -2adrenergic receptor (ADRB2) rslO42714, 1.2 or 2.2(C/G or G/G) (27 glutamic acid (27Glu)) or β -2adrenergic receptor (ADRB2) rslO42714, 1.1(C/C) (27 glutamine/glutamine) bound to β -2adrenergic receptor (ADRB2) rslO42713, 2.2(a/a) (16 arginine/arginine) and adrenergic β -3 receptor (ADRB3) rs4994, 1.1(T/T) (64 tryptophan/tryptophan). Such subjects absorb more dietary fat and tend to store them in adipocytes, rather than consuming them during metabolism. These subjects showed normal energy metabolism response to regular exercise, thereby achieving their weight management goals. The presence rate of these complex genotypes in caucasians was 5%.

Composite genotype pattern # 3-responds to carbohydrate restriction, to exercise: a host carrying a peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282(12AIa /) 1.2 or 2.2(C/G or G/G) and/or β -2adrenergic receptor (ADRB2) rslO42714(27 glutamic acid (27Glu) /) 1.2 or 2.2(C/G or G/G) genotype, and a host carrying a peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282(12AIa /) 1.2 or 2.2(C/G or G/G) and fatty acid binding protein 2 (farag 2) rsl799883(54 threonine /) 2.2 or 1.2(a/a or G/a) complex genotype. All of the above satisfactory genotypes are combined with β -2adrenergic receptor (ADRB2) rs1042713 (16 arginine/arginine) 2.2(A/A) and adrenergic β -3 receptor (ADRB3) rs4994(64 tryptophan/tryptophan) 1.1(T/T) to meet the requirements for responsiveness to exercise. Such subjects are able to gain and maintain body weight from high dietary carbohydrate intake and show signs of impaired glucose and insulin metabolism. These subjects showed normal energy metabolism response to regular exercise, thereby achieving their weight management goals. The presence rate of these complex genotypes in caucasians was 5%.

Composite genotype pattern # 4-responds to a fat and carbohydrate balanced diet with less responsiveness to exercise: a host carrying a complex genotype of fatty acid binding protein 2(FABP2) rsl799883(54 alanine/alanine) 1.1 or G/G and peroxidase proliferation factor activated receptor-gamma (PPARG) rsl801282(12 proline/proline) 1.1 or C/C and beta-2adrenergic receptor (ADRB2) rslO42713(16 glycine (16 Gly): 1.2 or 1.1(G/G or G/A) or adrenergic beta-3 receptor (ADRB3) rs4994(64 Arg) 1.2 or 2.2(C/T or C/C). This category includes subject genotypes known to be responsive to low-fat or low-carbohydrate, calorie-restricted diets, exhibiting weight variation. From the variants tested in the panel, these subjects did not show a consistent genetic trend towards injury when classified as fat in restricted diets or carbohydrate in restricted diets. They have impaired energy metabolism and respond less to regular exercise to achieve their weight management goals. These complex genotypes were present in caucasian adults at a rate of 14%.

Composite genotype pattern # 5-responds to fat restriction with less responsiveness to exercise: a host carrying a fatty acid binding protein 2(FABP2) rsl799883(54 threonine /) 2.2 or 1.2(a/a or G/a) and peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282(12 proline/proline) 1.1 or C/C and β -2adrenergic receptor (ADRB2) rslO42714(27 glutamic acid (27Glu)) 1.2 or 2.2(C/G or G/G) or β -2adrenergic receptor (ADRB2) rslO42714(27 glutamine/glutamine) 1.1(C/C) in combination with β -2adrenergic receptor (ADRB2) rslO42713(16 glycine (16 Gly)) 1.2 or 1.1(G/a or G/G) or adrenergic β -3 receptor (ADRB3) rs 94(64Arg 3) 492.94 or T2.1 or C2/C2. Such subjects absorb more dietary fat and tend to store them in adipocytes, rather than consuming them during metabolism. They have impaired energy metabolism and respond less to regular exercise to achieve their weight management goals. The expected presence ratio of these complex genotypes in caucasians was 34%.

Composite genotype pattern # 6-responds to carbohydrate restriction with less responsiveness to exercise: a host carrying a peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282(12AIa /) 1.2 or 2.2(C/G or G/G) and/or β -2adrenergic receptor (ADRB2) rslO42714(27 glutamic acid (27Glu) /) 1.2 or 2.2(C/G or G/G) genotype, and a host carrying a peroxidase proliferation factor activated receptor- γ (PPARG) rsl801282(12AIa /) 1.2 or 2.2(C/G or G/G) and fatty acid binding protein 2(FABP2) rsl799883 (threonine /) 2.2 or 1.2(a/a or G/a) complex genotype. All the above satisfactory genotypes are combined with β -2adrenergic receptor (ADRB2) rs1042713 (116 glycine (16Gly) × 1.2 or 1.1(G/a or G/G) or adrenergic β -3 receptor (ADRB3) rs4994(64 Arg) 2.1 or 2.2(C/T or C/C) to fulfill the requirement of less reactivity to locomotion. Such subjects are able to gain and maintain body weight from high dietary carbohydrate intake and show signs of impaired glucose and insulin metabolism. They have impaired energy metabolism and respond less to regular exercise to achieve their weight management goals. The presence rate of these complex genotypes in caucasians was 40%.

TABLE 7 host composite genotype and risk patterns

Receptor-gamma (PPARG) and fatty acid binding protein 2(FABP2), which represent peroxidase proliferation factor activation, are a complex genotype that targets weight management in the "response to fat restriction" category;

a genotype representing the term "less responsive to exercise" species;

represent the complex peroxidase proliferation factor activated receptor-gamma (PPARG), beta-2adrenergic receptor (ADRB2), or the peroxidase proliferation factor activated receptor-gamma (PPARG) + fatty acid binding protein 2(FABP2) genotype, which targets weight management in the category of "response to carbohydrate restriction".

Example 2: clinical gene typing method

DNA was extracted from buccal swabs (SOP #12, version 1.3) or purchased from Coriell cell banks. The isolated DNA was used to perform polymerase chain reaction to amplify the sequence region around five Single Nucleotide Polymorphisms (SNPs) (SOP # 29, version 1.0). 4 amplicons were obtained from each sample and treated with exonuclease I (Exo) and Shrimp Alkaline Phosphatase (SAP) to remove excess primers and nucleotides (SOP # 29, version 1.0). The purified amplicon was used to perform a single base extension reaction (SBE) in which primers specific for its Single Nucleotide Polymorphism (SNP) target were used (SOP # 30, version 1.0). Once the single base extension reaction (SBE) was completed, Shrimp Alkaline Phosphatase (SAP) was added again to remove unincorporated nucleotides (SOP # 30, version 1.0). The resulting single base extension reaction (SBE) products (SOP # 15, version 1.4 and SOP # 16, version 1.3) were analyzed on a Beckman Coulter CEQ8800 genetic analysis system with known standard migration dimensions. All genotypes were examined on the forward DNA strand, except for the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282). Peroxidase proliferation factor activated receptor-gamma (PPARG) (rs1801282) was detected on the reverse DNA strand and displayed as complement bases on a CEQ8800 sequencer. The resulting genotype was recorded and then compared to that produced using the DNA sequencer from Agencour biosciences, Inc., or to known genotypes recorded in NCBI. All genotypes were examined on the forward DNA strand, except for the peroxidase proliferation factor activated receptor-gamma (PPARG) (rsl 801282). Peroxidase proliferation factor activated receptor-gamma (PPARG) (rs1801282) was detected on the reverse DNA strand and displayed as complement bases on a CEQ8800 sequencer. The resulting genotype was recorded and then compared to that produced using the DNA sequencer from Agencour biosciences, Inc., or to known genotypes recorded in NCBI. Singleplex form: the host polymerase chain reaction product and the host genotyping were amplified separately by corresponding single base extension reaction (SBE) primers. Poolplex form: the bulk polymerase chain reaction products are amplified separately and then pooled together, and in a separate reaction, the pooled DNA is genotyped for all 5 Single Nucleotide Polymorphisms (SNPs) using single base extension reaction (SBE) primers. Multiplex format: all four polymerase chain reaction products are produced in a single reaction. In a separate reaction, the single base extension reaction (SBE) primer mix was used to determine the genotype of multiplexed DNA based on all 5 Single Nucleotide Polymorphisms (SNPs).

Standardization

A commercially available standard (Beckman Coulter part # 608395) was run with the samples as an internal reference for genotyping.

Accuracy and specificity

To ensure that the correct gene is targeted and the genotyping is performed accurately, the polymerase chain reaction products are submitted to a specialized laboratory (Agencourt biosciences) for sequencing and genotyping. In Agencourt, the test sequences were compared to genomic sequence side chain Single Nucleotide Polymorphisms (SNPs) and the genotype of each sample was reported to Interleukin Genetics. The results of Agencourt and Interleukin were compared for consistency.

Single Nucleotide Polymorphism (SNP) names and abbreviations

The following Single Nucleotide Polymorphism (SNP) names and abbreviations were used in this experiment: β -2adrenergic receptor (ADRB2) (R16G), rs1042713 ═ a 1; β -2adrenergic receptor (ADRB2) (Q27E), rs1042714 ═ a 2; adrenergic beta-3 receptor (ADRB3) (R64W), rs4994 ═ A3; fatty acid binding protein 2(FABP2) (a54T), rsl799883 ═ FA; peroxidase proliferator activated receptor- γ (PPARG) (P12A), rsl801282 ═ PP.

Results

PCR results

Isolated DNA was PCR amplified using the primers listed in appendix B. The β -2adrenergic receptor (ADRB2) (rslO42713) and β -2adrenergic receptor (ADRB2) (rslO42714) each have 33 nucleotides and are amplified on a single polymerase chain reaction product. The polymer chain reaction products were run on an agarose gel to examine the size of the expected products: a1/a2 base pair 422, A3 base pair 569, FA base pair 311, PP base pair 367.

Results of gene typing

Peak displacement

Individual Single Nucleotide Polymorphism (SNP) -specific single base amplification primers of unique length are designed to produce a peak at a specific site relative to a standard of known length when run on a CEQ8800 capillary electrophoresis apparatus. Due to dye migration, primer sequence and analysis software, primer size cannot match exactly to the peak site, but they do have consistent shifts. Single base amplification products are listed in appendix C along with their predicted peak shifts.

Base finding

Single base amplification reactions add a fluorescently labeled base to the 3' end of a Single Nucleotide Polymorphism (SNP) -specific primer. The resulting product was read by two lasers in CEQ 8800. The results were analyzed by the CEQ8800 software and expressed as coloured peaks-each colour represents a different base. The presence of a single color peak at a given site indicates the presence of a homozygote, and the presence of two different color peaks indicates the presence of a heterozygote. In thirty-nine samples that were genotyped, almost all homotypic and all heterotypic binding genotypes of five Single Nucleotide Polymorphisms (SNPs) have been represented. The only exception was the isotype-bound C genotype of the peroxidase proliferation factor activated receptor-gamma (PPARG) Single Nucleotide Polymorphism (SNP). This is not unexpected since the C allele usually occurs only 0.1 in the population (as shown in dbSNP database rs # _ 1801282). However, isotype-bound C genotypes have appeared in other samples outside of the present standard.

The CEQ8800 software enables the user to specify Single Nucleotide Polymorphism (SNP) site markers. The user can express the amount of displacement (in nucleotides) based on the predicted displacement of a Single Nucleotide Polymorphism (SNP) -specific primer. This enables the computer to recognize Single Nucleotide Polymorphisms (SNPs) based on the shift of a normalization marker that is run with the sample. The computer can also recognize a base within a Single Nucleotide Polymorphism (SNP) based on the detected dye indicator. For these criteria, the computer is able to initially map out individual Single Nucleotide Polymorphisms (SNPs). These data were then analyzed again independently, with confirmation by two professionals. In any case, the computer check and the two independent (manual) checks should be consistent.

Coriell sample

After single plex format genotyping for fifteen Coriell DNA samples, the results were compared to known genotype orientations to give 100% identity (see Table 8).

Table 8: genotyping results for Coriell samples

Table 8: the known genotype (Coriell) was compared to the genotype obtained from Interleukin Genetics (ILI) using the singleplex format with DNA from a Coriell cell library. Annealing a peroxidase proliferation factor activated receptor-gamma (PPARG) single base amplification primer along the reverse DNA strand direction. Thus, the ILI peroxidase proliferation factor activated receptor-gamma (PPARG) (rs1801282) bases are listed as a complement of the forward chain genotype, na ═ the genotype that could not be used by the Coriell cell library

While the invention has been described with respect to particularly preferred embodiments and examples, those skilled in the art will recognize that the invention can be practiced with many modifications without departing from the spirit and scope of the present invention.

All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data, are incorporated herein by reference, in their entirety.

Reference to the literature

Baier LJ, Sacchettini JC, Knowler WC, Eads J, Paolisso G, Tatarani PA, Mochizuki H, Bennett PH, Bogardus C, and Prochazka M.an amino acid binding in the human internalinapty acid binding protein with associated failed acid binding, associated failed oxidation, and insulin resistance.J. Clin Invest 95: 1281-1287, 1995(Baier LJ, Sacchettini JC, Knowler WC, EardsJ, Paolisso G, Tararanni PA, Mochizuki H, Bennett PH, Bogardus C, and Prochazka M in 1995 "clinical Studies" at stage 95, page 1281-1287, entitled "documents in human intestinal fatty acid binding proteins in which amino acid substitutions are associated with increased fatty acid binding, increased fat oxidation and insulin resistance")

Levy E, Menard D, Delvin E, Stan S, Mitchell G, Lambert M, Ziv E, Feoli-Fonseca JC, and Seidman E. the polymorphism subcon 54 of the FABP2 genes involved in fat absorption in humanexpressed plants. J Biol Chem 276: 39679-

Hegele RA, Harris SB, Handey AJ, Sadikian S, Connelly PW, and Zinman B.genetic variation of endogenous fat acid-binding protein associated with variation in body mass in antigenic canvas. J.Clin Endocrinol Metab 81: 4334 ℃ 4337, 1996 (HegeleRA, Harris SB, Hanley AJ, Sadikian S, Connelly PW, and Zinman B published in 1996 at "clinical endocrine and metabolism" journal 81: 4334 ℃ 4337. the paper entitled "genetic variation of the intestinal fatty acid binding protein associated with weight changes in indigenous residents in Canada")

Yamada K, Yuan X, Ishiyama S, Koyama K, Ichikawa F, Koyanagi A, Koyama W, and Nonaka K.Association beta. WeenAla54 simulation of the facial acid-binding protein 2gene with protein resistance and intra-anatomical face of the facial tissue in Japanese men 40: 706.. sup. -. 710, 1997(Yamada K, Yuan X, Ishiyama S, Koyama K, Ichikawa F, Koyanagi A, Koyama W, and Nonaka K. published in 1997 on "diabetes" at stage 40, 706. sup. -. 710, entitled "relationship between alanine 54 threonine substitution of fatty acid binding protein 2 in Japanese Male and insulin resistance and Intra-abdominal fat thickness")

Albala C, Santos JL, Cifuentes M, Villarroel AC, Lera L, Liberman C, Angel B, and Perez-Bravo F. endogenous FAB P2A54 Tpolymorphism: association with insulin resistance and ease in women Res 12: 340-

Pratley RE, Baier L, Pan DA, Salbe AD, Storlein L, Ravusin E, and Bogardus C.effects of an Ala54Thr polymorphism in the endogenous fat acid-binding protein on stresses to fat fats humans J Lipid Res 41: 2002- & ltSUB & gt 2008 & 2000.(Pratley RE, Baier L, Pan DA, Salbe AD, Storlien L, Ravusin E, and Bogardus C. A reference entitled "Effect of alanine 54 threonine polymorphism in intestinal fatty acid binding protein in dietary fat response" published in "lipid study" No. 41, 2002- & ltSUB & gt 2008 page 2000)

Agren JJ, Valve R, Vidgren H, Laakso M, and Uusitupa M.Postprandial lipid response is modified by the polymorphism subcon 54 of the failure acid-binding protein 2 gene. 1606-1610, 1998(Agren JJ, Valve R, Vidgren H, Laakso M, and Uusitupa M. published in 1998 on "ArteriosclerThromb vaso Biol" at stage 18 1606-1610 in the literature entitled "post-meal lipemic reaction modified by a polymorphism at codon54 of the fatty acid-binding protein 2 Gene")

Agren JJ, Vidgren HM, Valve RS, Laakso M, and Uusitupa MI.Postprandial responses of subject facial acids in subject facial zygous for the same hormone-or hormone-amino binding enzyme in code 54 of the same facial acid binding protein 2 gene. am J Clin Nutr 73: 31-35, 2001(Agren JJ, Vidgren HM, Valve RS, Laakso M, and Uusitupa MI. in 2001, published on "J.Clin.Nutrition" pp.73.31-35, USA J.Clin.Ouchi-Nutrition "entitled" Homomodebinding of alleles encoding threonine or alanine at codon54 of fatty acid binding protein 2Gene in vivo fatty acid reaction after meal in subjects ")

Lefevre M, Lovejoy JC, Smith SR, Delay JP, Champagne C, Most MM, Denkins Y, de Jonge L, Rood J, and Bray GA.Comparison of the access response to media encoded with cis-orthons-fastidions access on glucose and lipids in overhead subjects with differential FABP2 genetics. Metabolism 54: 1652-1658, 2005(Lefevre M, Lovejoy JC, Smith SR, Delay JP, Champagne C, Most MM, Denkins Y, de Jonge L, Rood J, and Bray GA., published in 2005 at "metabolism" stage 54, 1652-1658, under the name "comparison of Rapid reactions to meat, dextran and lipids rich in cis-or trans-fatty acids in hosts carrying different FABP2 genotypes")

De Luis DA, Aller R, Izaola O, Gonzalez Sagrado M, and Conde R. infiluence of ALA54THR Polymorphism of Fatty acid binding Protein 2 on Life style Modification in asphalt Subjects. Ann Nutr Metab 50: 354 + 360, 2006(de Luis DA, Aller R, Izaola O, Gonzalez Sagrado M, and Conde R published 1006 in "annual nutrition and metabolism" 50 th stage 354 + 360 entitled "response of fatty acid binding protein 2 alanine 54 threonine polymorphism to lifestyle modification in obesity subjects")

Marin C, Perez-Jimenz F, Gomez P, Delgado J, PaniaA, Lozano A, cortex B, Jimenez-Gomez Y, Gomez M, Lopez-Miranda J.the ala54 polyraphis of the fat acid-binding protein 2gene is associated with a changed in sensitive enzyme change in the type of diet fat.am J.CHn.Nutr 82: 196.. sup. (Marin C, Perez-Jimenz F, Gomez P, Delgado J, Paniagua A, Lozano A, cortex B, Jimenez-Gomez Y, Gomez M, Lopez-Miranda J. reference entitled "fatty acid binding protein 2 alanine 54 threonine polymorphism associated with insulin sensitivity Change after changing dietary fat type" published in 2005 at "Am J CHn Nutr" page 82, 196- "page 200)

Takakura Y, Yohsioka K, Umekawa T, Kogure A, Toda H, Yoshikawa T, Yoshida T.Thr54allel of the FABP2gene infectious quenching metabolic rate and scientific ease of Research, diabetes Research and pharmaceutical Practice 67: 36-42, 2005.(Takakura Y, Yohsioka K, Umekawa T, Kogure A, Toda H, Yoshikawa T, Yoshida T. published in 2005 at "diet research and clinical practice" pp.67, 36-42 entitled "FABP 2Gene threonine 54allele affects resting metabolic rate and visceral obesity")

Jones JR, Barrick C, Kim K-A, Linder J, Blindeau B, et al, Deletion of PPAR γ in adipose tissues of micro detectors as an ingredient high fat di-induced organism and insulin resistance PNAS 102: 6207-6212, 2005 (Jones JR, Barrick C, Kim K-A, Linder J, Blondeau B, et al, 2005, the publication entitled "deletion of PPAR γ in adipose tissue of mouse animal at" PNAS "No. 102, 6207-6212" for prevention of high fat diet-induced obesity and insulin resistance

Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, and Auwerx J.A Pro 12 AIasubstistition in PPARgamma2 associated with created receptor activity, lower body mass index and created antigen sensitivity Nat Gene 20: 284-287, 1998 (Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, and Auwerx J. A reference entitled "proline 12 alanine substitution on PPAR γ 2 associated with reduced receptor activity, lower body mass index, and improved insulin sensitivity", published in 1998 at "Natural genome" page 20-284-287)

Rankine T, Zuberi A, Chagnon YC, Weissagel J, Argyropoulos G, et al, the human organism gene map: the 2005update. 529 + 644(Rankine T, Zuberis A, Chagnon YC, Weissagel J, Argyropoulos G, et al, obesity 14, 529 + 644, entitled "human obesity Gene Spectrum: 2005update edition)

Robitaille J, despress JP, Perusse L, and Vohl MC, the PPAR-gamma P12A polymeric modifications the relationship between the two sets of the two: results from the Quebec Family study. Clin Genet 63: 109- & ltCHEM & gt 116,2003 (Robitailel J, despires JP, Perusse L, and Vohl MC. published in 2003 at "clinical genes" No. 63, page 109- & ltCHEM & gt 116 entitled "relationship between PPAR γ P12A polymorphism regulating dietary fat intake and metabolic symptom components: results obtained from Kuebeck family research")

Memisoglu a, Hu PJ, Hankinson SE, Manson JE, De Vivo I, Willet WC, and Hunter dj. interaction between a peroxisome promoter-activated receptor gamma gene expression in interaction to body mass 12: 2923-2929, 2001(Memisoglu A, Hu PJ, Hankinson SE, Manson JE, De Vivo I, Willet WC, and Hunter DJ. in 2001, at 2923-12 th of "human molecular genetics", the document entitled "relationship between polymorphism of peroxidase proliferation factor-activated receptor-gamma gene and dietary fat intake" was published)

Lindi VI, Uusitupa MI, Lindstrom J, Louheranta A, Eriksson JG, Valle TT, Hamalainen H, Ilane-Parikka P, Keinanen-Kiukaanniemimi S, Laakso M, and Tuomilahto J. Association of the Pro 12AIa polymorphism in the PPAR-gamma2gene with 3-near identity of type 2Diabetes and body weight change in the Finnish Diabetes prediction Studies 51: 2581-A2586, 2002(Lindi VI, Uusitupa MI, Lindstrom J, LouherantaA, Eriksson JG, Valle TT, Hamalainen H, Ilane-Parikka P, Keinanen-Kiukananiemi S, Laakso M, and Tuomilehto J. A reference published in 2002 at "diabetes" No. 51 2581-A2586 entitled "relationship between Pro 12 alanine polymorphism of the Perperoxidase Proliferation factor activated receptor-gamma2Gene and type 2diabetes of 3 annual incidence and weight Change in the Finnish diabetes prevention study")

Nicklas BJ, van Rossum EF, Berman DM, Ryan AS, DennisKE, and Shuldiner AR. genetic variation in the peroxisome promoter-activated receptor-gamma2gene (Pro 12AIa) infectious metabolic disorders to weight loss and subset weight gain reagents. diabetes 50: 2172-2176, 2001(Nicklas BJ, van Rossum EF, Berman DM, Ryan AS, Dennis KE, and Shuldiner AR. and 2001 at "diabetes" stage 50, page 2172-2176 entitled "Metabolic response to weight loss and subsequent weight gain by Perperoxidase Proliferative factor activated receptor-Gamma2Gene alteration (proline 12 alanine)

Meirhaeghe A, Helbecque N, Cotte D, Amouyel P.Impactor polymorphism of the human β 2-adrenoceptor gene on organism in a French utility.Intl J Obesity 24: 382-87, 2000(Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. A reference entitled "Effect of polymorphism of human beta-2adrenergic receptor Gene on obesity in French" International obesity "at No. 24, page 382-387

Green SA, Turki J, Innis M, and Liggett SB, amino-tertiary polymorphism of the human beta2-adrenoceptor animal diagnosis agonist-protein regulation protocols, biochemistry 33: 9414-9419, 1994(Green SA, Turki J, Innis M, and Liggett SB published 1994 "Biochemical" at stage 33, page 9414-9419, entitled "amino terminal polymorphism of human β -2adrenergic receptor affecting the regulatory Properties promoted by different agonists")

Hellstrom L, Large V, Reynisdottir S, Wahrenberg H, inner P.the differential effects of a Gln27Glu B2-antireflective gene polymorphism on ease in maps and maps.J. Intern Med 245: 253-259, 1999(Hellstrom L, Large V, Reynisdottir S, Wahrenberg H, Arner P, 1999 in "J.International medicine" at stage 245, page 253-259, entitled "different effects of the polymorphism of the beta-2adrenergic receptor Gene Glutamine 27glutamic acid on obesity in Male and female

Garenc C, Perusse L, Chagnon YC, Rankine T, Gagnon J, Boreki IB, Leon AS, Skinner JS, Wilmore JH, Rao DC, andBrouchard C.Effect of beta 2-iterative receiver gene variables online: the HERITAGE Family study. Obes Res 11: 612- & ltCHEM & gt 618, 2003(Garenc C, Perusse L, Chagnon YC, Rankine T, Gagnon J, Boreki IB, Leon AS, Skinner JS, Wilmore JH, Rao DC, and Bouchard C. A reference entitled "Effect of beta-2adrenergic receptor Gene variants on obesity" & ltD & gt 612 & 618, 11 th of the obesity study in 2003: genetic family study ")

Lange LA, Norris JM, Langefeld CD, Nicklas BJ, Wagenknecht LE, Saad MF, and Bowden DW. Association of adipose tissue disposition and beta-2 acquired receptor variants: int J Obes (Lond) 29: 449-457 (Langela, Norris JM, Langefeld CD, Nicklas BJ, Wagenknecht LE, Saadmf, and Bowden DW. published 2005 in "J.In. obesity" pp 29 th 449: IRAS family research "the document entitled" relationship between adipose tissue digestion and beta-2adrenergic receptor variants: "IRAS family research")

Gonzalez Sanchez JL, Proenza AM, Martinez Larrad MT, Ramis JM, Fernandez Perez C, Palou A, and Serrano Rios M.the glutamine 27glutamic acid polymorphism of the beta 2-acquired vector with absolute activity and grease of amplified glucose tolerance in the mean butyl in a watch: cloning-based study in Spain. Clin endocrine (Oxfi 59: 476-481, 2003) (Gonzalez Sanchez JL, Proenza AM, Martinez Larrad MT, Ramis JM, Fernandez Perez C, Palou A, and Serrano Rios M. A polymorphism of the beta-2adrenergic receptor glutamine 27glutamic acid published in 2003 on page 476-481 of "clinical Endocrinology" 59, related to male abdominal obesity and to a greater risk of impaired glucose tolerance, but not female: Studies in Spain:)

Masuo K, Katsuya T, Kawaguchi H, Fu Y, Rakuga H, et al, b 2-autoreceptor polymorphism release to issue through blueness blundnectin-mediated pathological activity am jjhexertens, 19: 1084-91, 2006 (Masuo K, Katsuya T, Kawaguchi H, Fu Y, Rakuga H, et al published 2006 at "Am JHP ertens" at page 19, 1084-91, entitled "sympathetic activation mediated by blunt leptin, beta-2adrenergic receptor polymorphism associated with obesity")

Ellsworth DL, Coady SA, Chen W, Srinivasan SR, Elkasabany A, Gustat J, Boerwinkle E, and Berenson GS. infinence of the beta 2-anergic receiver Arg16Gly polymorphism on longitudinal changes in ease from bone through bone great birth in biological family a biological family: int J obesrelt meta disorder 26: 928-937, 2002(Ellsworth DL, Coady SA, Chen W, Srinivasan SR, Elkasabany A, Gustat J, Boerwinkle E, and Berenson GS. in 2002, published by the title "Effect of beta-2adrenergic receptor arginine 16 glycine polymorphism on longitudinal changes from childhood to juvenile obesity" in the International journal of obesity and related Metabolic diseases "at page 26, 928-937)

Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, and TuckML beta2-and beta 3-acquired receptor polymorphism associated to the onset of weight gain and blood pressure elevation overview. circulation 111: 3429-3434, 2005(Masuo K, Katsuya T, FuY, Rakugi H, Ogihara T and Tuck ML et al, 2005, at "circulation" stage 111, 3429-3434, a document entitled "relationship between polymorphisms of the beta-2adrenergic receptor and beta-3 adrenergic receptor and weight gain and blood pressure elevation within 5 years")

Van Rossum CT, Hoebee B, Seidell JC, Bouchard C, van Baak MA, de Groot CP, Chagnon M, de Graaf C, and Saris WH. 517-528, 2002(van Rossum CT, Hoebee B, Seidell JC, Bouchard C, van BaakMA, de Groot CP, Chagnon M, de Graaf C, and Saris WH et al, in 2002, published on page 517-528 of the journal of International obesity and related Metabolic diseases, "in the Netherlands, Male and female younger people" under the name "using genetic factors as weight prediction factors in Netherlands

Martinez JA, Corbalan MS, Sanchez-Villegas A, Forga L, Marti A, and Martinez-Gonzalez MA. besity isk is associated with carbohydrate inter-cut in mouse heart of the Gln27Glubeta 2-adrenocepter polymorphism. JN Jutr 133: 2549-

Ukkola O, Tremblay A, and Bouchard C.beta-2 advanced detector variant area associated with sub-areas failure association in response to long-term overlapping. int J-Obes Relat Metab disorder 25: 1604-

Corbalan MS, the 27Glu polymorphism of the beta 2-acquired receptor genes with a physical activating reflecting object, clin Gene 61: 305-307, 2002 (Corbalan MS published 2002 in "clinical genomics" No. 61-305-307 of Corbalan MS under the name "interaction between the polymorphism of glutamate in the beta-2adrenergic receptor gene 27 and physical activity affecting the risk of developing obesity in female subjects")

Umekawa T, Yoshida T, Sakane N, Kogure A, Kondo M, and Honjyo H. Arg64Trp mutation of beta3-adrenoceptor genes induced by beta3-adrenoceptor agonist in genomic antigens, diabetes 48: 117- & ltCHEM & gt 120,1999 (UmekawaT, Yoshida T, Sakane N, Kogure A, Kondo M, and Honjyo H, published in 1999 on "diabetes mellitus" stage 48, page 117- & ltwbr & gt 120, entitled "degeneration of lipid hydrolysis ability caused by beta-3 adrenergic receptor antagonist in human retinal adipocytes due to arginine 64 threonine mutation of beta-3 adrenergic receptor gene

Hoffstedt J, poinier O, Thorne a, Lonnqvist F, HerrmannSM, Cambien F, and Arner p. polymorphism of the humanbeta 3-acquired gene for ms a well-collected connected portable type of associated with modified object 48: 203-205, 1999(Hoffstedt J, Poirier O, Thorne A, Lonnqvist F, Herrmann SM, Cambien F, and Arner P. published 1999 on "diabetes" page 48-203-205, entitled "polymorphisms in the human beta-3 adrenergic receptor Gene form a well-protected haploid associated with moderate obesity and altered receptor function")

Allison DB, Heo M, Faith MS, and Pietrobelli A. Meta-analysis of the association of the Arg64Trp polyrorphism inter-he beta3 acquired receptor with body mass index. int J inserts Relatilbetab disease 22: 559-566, 1998 (Allison DB, Heo M, Faith MS and Pietrobelli A. A reference entitled "Meta-analysis of the relationship between arginine 64 threonine polymorphism of the beta-3 adrenergic receptor gene and body Mass index", published in 1998 at "the journal of obesity and related Metabolic diseases" No. 22, p. 559-566)

Fujisawa T, Ikegami H, Kawaguchi Y, and Ogihara T.Meta-analysis of the association of Arg64Trp polyrorphism of beta 3-acquisition receptor gene with body mass index J.Clin EndocrinolMetab 83: 2441-2444, 1998(Fujisawa T, Ikegami H, Kawaguchi Y, and Ogihara T in 1998 at "clinical endocrine and metabolism" stage 83, 2441-2444 entitled "Meta-analysis of the relationship between arginine 64 threonine polymorphism of beta-3 adrenergic receptor gene and body Mass index")

Kurokawa N, Nakai K, Kameo S, Liu ZM, and Satoh H.Association of BMI with the beta 3-acquired receptor genetic polymorphism in Japanese: meta-analysis. obes Res 9: 741-

Marti a, Corbalan MS, Martinez-Gonzalez MA, and Martinez ja. arg64trp polymorphism of the beta 3-anenergiceceptor gene and ease risk: effect modification by a condensation, diabetes, Obes, metabes, meta 4: 428-

Sakane N, Yoshida T, Umekawa T, Kogure A, Takakura Y, and Kondo M.Effect of Arg64Trp mutation in the beta 3-iterative receiver gene on weight loss, body fat distribution, physiological control, and insulin resistance in object type 2diabetes properties. 1887-type 1890, 1997(Sakane N, Yoshida T, Umekawa T, Kogure A, Takakura Y, and Kondo M. published in 1997 on "diabetes Care" stage 20 1887-type 1890, a reference entitled "Effect of the arginine 64 threonine polymorphism of the β -3 adrenergic receptor Gene on weight loss, body fat distribution, glycemic control and insulin resistance in obese type II diabetic patients")

Shiwaku K, Nogi A, Anuurad E, Kitaj ima K, Enkhmaa B, Shimono K, and Yamane Y.Difficulty in positioning weight by behavirological interaction for world with Arg64Trp polyraphism soft word 3-adaptive receiver gene. int J Obbes Relat Metab D27: 1028-

Phares DA, Halverstadt AA, Shuldiner AR, Ferrell RE, Douglass LW, Ryan AS, Goldberg AP, and Hagberg JM.Association between body fat response to interaction transmitting and culturing ADR genes Obes Res 12: 807-

Southern of A, Starling RD, Walston JD, Shuldiner AR, et al, object-related languages and the β 3-adrenoceptor gene variant in spatial genome 48: 1425-1428, 1999(Tchern A, Starling RD, Walston JD, Shuldiner AR, et al, 1999 in "diabetes" stage 48 1425-1428, the literature entitled "obesity-related phenotypes in postmenopausal women and. beta. -3 adrenergic receptor Gene variants")

Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, and Auwerx J.A Pro 12 AIasubstistition in PPARgamma2 associated with created receptor activity, lower body mass index and created antigen sensitivity Nat Gene 20: 284- & ltCHEM > 287, 1998 (Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, and Auwerx J. published in 1998 at "Natural Gene" stage 20, page 284- & ltSUB & gt 287, entitled "Perperoxidase proliferation factor activated receptor associated with reduced receptor activity, lower body Mass index, and improved insulin sensitivity-Pro 12 alanine substitution of the γ 2 Gene")

Masugi J, Tamori Y, Mori H, Koike T, and Kasuga M.inhibitoray effect of a proline-to-alanine inhibition at code 12 of peroxisome proliferator-activator-activated receptor-gamma2 on thiolated-induced antigen. biochem Biophys research is.178-182, 2000 (Masugij, Tamori Y, Mori H, Koike T, and Kasuga M. published in 2000 under the name "biochem research and biophysics exchange at page 182" 178-178 "entitled" inhibition of thiazolidinedione-induced lipogenesis by substitution of proline-alanine at codon 12 of receptor-gamma2 activated by peroxidase proliferation factor ")

45.Kahara T, Takamura T, Hayakawa T, Nagai Y, Yamaguchi H, Katsuki T, Katsuki K, Katsuki M, and Kobayashi K.PPARgamma gene polymorphism is associated with modulated-sized changes of insulin resistance in fatty men 52: 209-212, 2003 (Kahara T, Takamura T, HayakawaT, Nagai Y, Yamaguchi H, Katsuki T, Katsuki K, Katsuki M, and Kobayashi K. A document entitled "peroxidase proliferation factor-activated receptor-gamma gene polymorphism associated with exercise-mediated insulin resistance changes in healthy males" published at "metabolism" stage 52, page 209-212 in 2003)

Adamo KB, Sigal RJ, Williams K, Kenny G, Prud' hommeD, and Tesson F. influx of Pro 12AIa peroxisome promoter-activated receptor gamma2 polyraphin glucose metabolism to excretion metabolism in type 2diabetes 48: 1503 ℃ 1509, 2005 (Adamo KB, Sigal RJ, Williams K, Kenny G, Prud' homme D, and Tesson F. A publication entitled "Effect of peroxidase proliferation factor-activated receptor-gamma2 proline 12 alanine polymorphism on exercise-trained glucose response in type II diabetic patients" published in 2005 "Glycurology" at page 48 1503 ℃ 1509)

Weiss EP, Kulaputana O, Ghiu IA, Brandauer J, Wohn CR, Phares DA, Shuldiner AR, and Hagberg JM.Endurancetraining-induced changes in the insulin response to organic glucose in vivo efficacy with the peroxisome promoter-activated receptor-gamma2 Prol2Ala genetic in men button in mouse 54: 97-102, 2005.(Weiss EP, Kulaputana O, Ghiu IA, Brandauer J, Wohn CR, Phares DA, Shuldiner AR, and Hagberg JM. published in 2005 at "metabolism" pages 97-102, entitled "altered response of insulin to oral glucose induced by endurance training is associated with the peroxidase proliferation factor-activated receptor γ 2 proline 12 alanine genotype in men, but not women.)

Guittier J, Georgopoulos A, Tsai M, Ratha V, Shanthrani S, deep R, Gross M, Rao G, Mohan V.polymorphism in the facial-binding protein 2and apolipoprotein c-III genes are associated with the metabolic syndrome and dyslipidemia in a solution Indianop. J.Clin endocrine ab 90: 1705-

Pollex R, Hanley A, Zinman B, Harris S, Khan H, Hegel R.Metabolic syndrome in antigenic Canadians: predictive and architectural dependencies 184: 121- & gt129, 2006 (Pollex R, Hanley A, Zinman B, Harris S, Khan H, Hegele R, 2006, published in "atherosclerosis" journal 184 th page 121- & 129, page 121- & ltJ & gt, Canada indigenous residents, the literature entitled "prevalence and Gene relevance")

Karani S, Radha V, Mohan V.Thr54allel carriers of the Ala54 variant of FABP2gene having associations with ligands and ultragenes in uracil South industries, Metabolim Clinical and Experimental 55: 1222. 12226, 2006 (Karani S, Radha V, Mohan V, published 2006 at "clinical and laboratory metabolism" page 55: 1222. 1226 of the document entitled "threonine 54allele carrier carrying alanine 54 threonine variant of FABP2Gene is associated with the metabolic syndrome and hypertriglyceridemia of south Indian town residents

Pereira M, Swain J, Goldfine A, Rifai N, Ludwig D. Effect a low-physiological load di et on restraining energy ex-dependent and heartly differential factors weight loss. JAMA 292 (20): 2482-

Hallikainen M, Toplinen L, Mykkanen H, Agren J, Laakonen D, Miettinen T, Niskanen L, Poutanen K, Gylling H. interaction between phenol polyol and glucose lipid degradation in subjects with the metabolism carbohydrate, am J Clin Nutr 84: 1385-1392, 2006 (Hallikainen M, Toppinen L, Mykkanen H, Agren J, Laaksonen D, Miettinen T, Niskanen L, Poutanen K, Gylling H. A publication entitled "interrelation of cholesterol and glucose metabolism during dietary carbohydrate modification in patients with metabolic syndrome" published in 2006 "journal of clinical Nutrition" No. 84-1385-1392)

53.Kallio P, Kolehmain M, Laaksonen D, Kekalainen J, Salopuro T, Sivenius K, Pulkkinen L, Mykkanen H, Niskanen L, Uusitupa M, Poutanen K.dietary carbohydrate modification indexes in gene expression in antibody sub-genes adhesives in proteins with the metallic synthesis: am JCHn Nutr 85: 1417-

Paradis A-M, Fontaine-Bisson B, Bosse Y, Robitaille J, Lemieux S, Jaques H, Lamarche B, Tcherof A, Couture P, VohlM-C, The peroxisome promoter-activated receptor alpha Leu 62. polyol reactivity information to a catalytic interaction evaluation failure acid in molecular reactor Am. JClin Nutr 81: 523-30, 2005.(Paradis A-M, Fontaine-Bisson B, Bosse Y, Robitaille J, Lemieux S, Jaques H, Lamarche B, Tchernofa, Couture P, Vohl M-C in 2005, 523 & 530 of the J.Clin.S.J.Clin.Nutrition, pp.81 & 530 entitled "peroxidase growth factor activated receptor-. alpha.leucine 162 valine polymorphism affecting the metabolic response of healthy males to dietary interventions with altered fatty acid ratios")

Macho-Azcarate T, Marti A, Gonzalez A, Martinez JA, Ibenez J.Gln27Glu polymorphism in the beta2 acquired recombinant gene and lipid metabolism during excretion in organism. 1434-41, 2002 (Macho-Azcarate T, Marti A, Gonzaleza A, Martinez JA, Ibenez J published in 2002 at 1434-1441 of the International journal of diabetes, 26 th page, entitled "polymorphisms in the β -2adrenergic receptor Gene Glutamine 27 glutamate and lipid metabolism during exercise in obese women")

56.Kahara T, Hayakawa T, Nagai Y, Shimizu A, Takamura T.Gln27Glu polymorphism of the β 2 acquired receptor gene expression in Japanese patent men is associated with the change of structural analysis used by expression Res clean Practice 64: 207-12, 2004 (Kahara T, Hayakawa T, Nagai Y, Shimizu A, Takamura T. A reference entitled "polymorphism of Glutamine 27glutamic acid in the Gene Glutamine of the β -2adrenergic receptor in healthy Japanese Male associated with changes in fructosamine brought about by exercise", published in 2004 on "diabetes research and clinical practice" No. 64, 207-

Marti A, Corbalan MS, Martinez-Gonzalez MA. CHOintetake optics associated with Prol2Ala polymorphism of PPARG gene. J. physiol. biochem., 58 (4): 219- & ltSUB & gt 220 & lt 2002. & gt (MartiA, Corbalan MS, Martinez-Gonzalez MA. in 2002, journal of physiological biochemistry 58 & lt 4 & gt: 219- & gt 220, published by the reference entitled "alteration of carbohydrate intake at risk of obesity associated with proline 12 alanine polymorphism of PPARG Gene

58.Centers for Disease Control and Prevention，available athttp://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm.Accessed 10/21/07.

59.National Center for Health Statistics，available at http://www.cdc.gov/nchs/fastats/overwt.htm.Accessed 10/21/07.

Flegal KM, Carroll MD, Ogden CL, Johnson CL.prevalence and tresds in importance US additions, 1999-2000.JAMA, 288: 1723-

61.Ogden CL, Carroll MD, Curtin LR, McDowell MA, TabakCJ, Flegal KM.Presence of overhead and opportunity in the United states, 1999-2004 JAMA, 295: 1549-

Ogden CL, flagal KM, Carroll MD, Johnson cl.prevalence and tresds in overlapping weight among US children and daloleces, 1999-2000, JAMA 288: 1728-

63.Centers for Disease Control and Prevention，available athttp://wwwxdc.gov/nccdphp/dnpa/obesity/consequences.htrn.Accessed 10/21/07.

64.Centers for Disease Control and Prevention，available athttp://www.cdc.gov/nccdphp/dnpa/obesity/economicconsequences.htm.Accessed 10/21/07.

65.WoifAM, Colditz GA. Current estimates of the environmental estimates in the United states. Obes Res 6: 97-106, 1998 (WoifAM, Colditz GA. in 1998 at stage 6 of the obesity research, pages 97-106 entitled "currently projected costs of American obesity")

66.Finkelstein, EA, Fiebelkorn, IC, Wang, G.national media pending attribute to overhead and opportunity: how much moch, and whho's shipping? Health affaires suppl.w3; 219- & ltCHEMLstein, EA, Fiebelkorn, IC, Wang, G in 2003, published on "health affairs support" journal, page W3, 219- & ltD & gt 226, entitled "cost of the national medical System in terms of overweight and obesity & ltD & gt, and who paid")

U.S. department of Health and Human services, the surgery General's Call to Action to present and discovery overview and Obesistance, Rockville, MD: department of Health Services, Public Health Service, Office of the surgery general; 2001. (department of health and public service, Ministry of health authorities required action to prevent or reduce overweight and obesity, Rockville, MD: department of health and public service, public health service, office of health authorities, 2001)

68.Johnson R, Williams S, Spruill I.genomics, nutrition, obesity and diabetes.J Nurs Schlarsh 38: 11-18, 2006 (Johnson R, Williams S, Spruill I. published in 2006 at "J Nurs Scholarsh" pages 11-18, 38 entitled "genomics, Nutrition, obesity and diabetes")

Frosch D, Mello P, leman c. behavial sequences for influencing risk. cancer epidemic biomerkers Prev 14: 1485-1489, 2005 (Frosch D, Mello P, Lerman C. published 2005 on "Cancer epidemic Biomarkers Prev" page 14-1485-1489 of the document entitled "obesity Risk persistence test")

BMI Classification of World Health organization (BMI Classification)

Claims

1. A kit, comprising: a) according to FABP2(rsl 799883; G/A), PPARG (rsl 801282; C/G) and ADRB2(rs 1042714; C/G) a reagent for determining the subject's metabolic genotype at the polymorphic site; and, b) instructions for determining the subject's metabolic genotype, and means for classifying the subject into a nutritional category that predicts the likely benefit to be obtained by the subject on a low fat diet.

2. The kit of claim 1, wherein the subject metabolic genotypes of ADRB2 glutamic acid 27, PPARG 12 proline/proline, and FABP 254 threonine/, categorize the subject into a nutritional class that is directed towards predicting the beneficial effects likely to be obtained by the subject from a low fat diet.

3. The kit of claim 1, further comprising reagents for determining the metabolic genotype of the subject based on the ADRB3(rs 4994; C/T) site or the ADRB2(rsl 042713; A/G) site.

4. The kit of claim 1, further comprising reagents for determining the subject's metabolic genotype based on the ADRB3(rs 4994; C/T) site and the ADRB2(rsl 042713; A/G) site.

5. The kit of claim 1, further comprising at least one reference sample selected from the group consisting of a positive reference sample and a negative reference sample.

6. The kit of claim 1, further comprising a DNA sampling tool and/or PCR reagents.

7. The kit of claim 1, further comprising at least one oligonucleotide, the oligonucleotide is selected from the group consisting of 5 'TGTTCTTGTGCAAAGGCAATGCTACCG 3' (SEQ ID NO: 1), 5 'TCTTACCCTGAGTTCAGTTCCGTCTGC 3' (SEQ ID NO: 2), 5 'GCCCCTAGCACCCGACAAGCTGAGTGT 3' (SEQ ID NO: 3), 5 'CCAGGCCCATGACCAGATCAGCACAG 3' (SEQ ID NO: 4), 5 'AAGCGTCGCTACTCCTCCCCCAAGAGC 3' (SEQ ID NO: 5), 5 'GTCACACACAGCACGTCCACCGAGGTC 3' (SEQ ID NO: 6), 5 'TGCCAGCCAATTCAAGCCCAGTCCTTT 3' (SEQ ID NO: 7), 5 'ACACAACCTGGAAGACAAACTACAAGAGCAA 3' (SEQ ID NO: 8), 5 'GAAGGAAATAAATTCACAGTCAAAGAATCAAGC 3' (SEQ ID NO: 9), 5 'AACGGCAGCGCCTTCTTGCTGGCACCCAAT 3' (SEQ ID NO: 10), 5 'AGCCATGCGCCGGACCACGACGTCACGCAG 3' (SEQ ID NO: 11), 5 'GGGAGGCAACCTGCTGGTCATCGTGGCCATCGCC 3' (SEQ ID NO: 12), and 5 'GACAGTGTATCAGTGAAGGAATCGCTTTCTG 3' (SEQ ID NO: 13).

8. The kit of claim 7, wherein said oligonucleotide comprises a detectable label.