[go: up one dir, main page]

WO2011116244A2 - Méthodes de diagnostic et de traitement d'affections associées à la clairance métabolique de l'insuline - Google Patents

Méthodes de diagnostic et de traitement d'affections associées à la clairance métabolique de l'insuline Download PDF

Info

Publication number
WO2011116244A2
WO2011116244A2 PCT/US2011/028902 US2011028902W WO2011116244A2 WO 2011116244 A2 WO2011116244 A2 WO 2011116244A2 US 2011028902 W US2011028902 W US 2011028902W WO 2011116244 A2 WO2011116244 A2 WO 2011116244A2
Authority
WO
WIPO (PCT)
Prior art keywords
seq
mcri
risk variants
genetic
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/028902
Other languages
English (en)
Other versions
WO2011116244A3 (fr
Inventor
Mark O. Goodarzi
Kent D. Taylor
Jerome I. Rotter
Thomas A. Buchanan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cedars Sinai Medical Center
University of Southern California USC
Original Assignee
Cedars Sinai Medical Center
University of Southern California USC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cedars Sinai Medical Center, University of Southern California USC filed Critical Cedars Sinai Medical Center
Publication of WO2011116244A2 publication Critical patent/WO2011116244A2/fr
Publication of WO2011116244A3 publication Critical patent/WO2011116244A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the invention relates generally to metabolic disorders and more specifically to the metabolic clearance rate of insulin.
  • MCRI metabolic clearance rate of insulin
  • Proatherogenic effects of insulin include stimulation of proliferation of vascular smooth muscle cells, while in contrast, insulin may protect against atherosclerosis by antagonizing inflammatory transcription factors.
  • the elucidation of genetic determinants of MCRI will provide insight into not only how insulin is cleared but also the mechanisms of insulin action. (Goodarzi, et al., Diabetes Vol. 54, pp 1222- 1227, April 2005). Thus, there is a need in the art to discover genetic determinants of MCRI as well as further explore their mechanisms and functional components.
  • Figure 2 Representation of 8 of the 88 SNPs that were replicated and found to be associated with MCRI.
  • Figure 4 Representation of 15 SNPs in the CMIP genetic locus with demonstrated association with MCRI.
  • the invention provides a method of prognosing an abnormal metabolic clearance rate of insulin (MCRI) and/or associated conditions in a subject, comprising: obtaining a sample from the subject, determining the presence or absence of one or MCRI genetic risk variants at the ADAMTSL3, CMIP, CCDC137P, HRNBP3, ITGA6, and/or ZNF224 genetic locus, and prognosing abnormal MCRI and/or associated conditions based on the presence of one or more risk variants at the ADAMTSL3, CMIP, CCDC137P, HRNBP3, ITGA6, and/or ZNF224 genetic locus.
  • the risk variants at the ADAMTSL3 genetic locus are selected from the group consisting of SEQ. ID. NO.: 1, SEQ. ID.
  • the risk variants at the CMIP genetic locus are selected from the group consisting of SEQ. ID. NO.: 10, SEQ. ID. NO. 11 , SEQ. ID. NO.: 12, SEQ. ID. NO.: 13, SEQ. ID. NO.: 14, SEQ. ID. NO.: 15, SEQ. ID. NO.: 16, SEQ. ID. NO.: 17, SEQ. ID. NO.: 18, SEQ. ID. NO.: 19, SEQ. ID. NO.: 20, SEQ.
  • the one or more risk variants are selected from the group consisting of SEQ. ID. NO.: 26, SEQ. ID. NO.: 27, SEQ. ID. NO.: 28, SEQ. ID. NO.: 29, and SEQ. ID. NO.: 30.
  • the MCRI associated conditions are selected from the group consisting of hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and/or polycystic ovary syndrome.
  • the sample can be whole blood, plasma, serum, saliva, cheek swab, urine, or stool.
  • the invention provides a method of diagnosing susceptibility to an abnormal metabolic clearance rate of insulin (MCRI) and/or associated conditions in a subject, comprising: obtaining a sample from the subject, determining the presence or absence of one or MCRI genetic risk variants at the ADAMTSL3, CMIP, CCDC137P, HRNBP3, ITGA6, and/or ZNF224 genetic locus, and diagnosing susceptibility to abnormal MCRI and/or associated conditions based on the presence of one or more risk variants at the ADAMTSL3, CMIP, CCDC137P, HRNBP3, ITGA6, and/or ZNF224 genetic locus.
  • the risk variants at the ADAMTSL3 genetic locus are selected from the group consisting of SEQ. ID.
  • the risk variants at the CMIP genetic locus are selected from the group consisting of SEQ. ID. NO.: 10, SEQ. ID. NO. 1 1, SEQ. ID. NO.: 12, SEQ. ID. NO.: 13, SEQ. ID. NO.: 14, SEQ. ID. NO.: 15, SEQ. ID. NO.: 16, SEQ. ID. NO.: 17, SEQ. ID. NO.: 18, SEQ. ID. NO.: 19, SEQ.
  • the one or more risk variants are selected from the group consisting of SEQ. ID. NO.: 26, SEQ. ID. NO.: 27, SEQ. ID. NO.: 28, SEQ. ID. NO.: 29, and SEQ. ID. NO.: 30.
  • the MCRI associated conditions are selected from the group consisting of hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and/or polycystic ovary syndrome.
  • the sample can be whole blood, plasma, serum, saliva, cheek swab, urine, or stool.
  • the invention provides a method of treating an abnormal MCRI and/or associated conditions in a subject, comprising: obtaining a sample from the subject, determining the presence or absence of one or MCRI genetic risk variants at the ADAMTSL3, CMIP, CCDC137P, HRNBP3, ITGA6, and/or ZNF224 genetic locus, and treating the subject.
  • the risk variants at the ADAMTSL3 genetic locus are selected from the group consisting of SEQ. ID. NO.: 1, SEQ. ID. NO.: 2, SEQ. ID. NO.: 3, SEQ. ID. NO.: 4, SEQ. ID. NO.: 5, SEQ. ID. NO.: 6, SEQ. ID. NO.: 7, SEQ. ID.
  • the risk variants at the CMIP genetic locus are selected from the group consisting of SEQ. ID. NO.: 10, SEQ. ID. NO. 11 , SEQ. ID. NO.: 12, SEQ. ID. NO.: 13, SEQ. ID. NO.: 14, SEQ. ID. NO.: 15, SEQ. ID. NO.: 16, SEQ. ID. NO.: 17, SEQ. ID. NO.: 18, SEQ. ID. NO.: 19, SEQ. ID. NO.: 20, SEQ. ID. NO.: 21 , SEQ. ID. NO.: 22, SEQ. ID. NO.: 23, SEQ. ID. NO.: 24, and SEQ. ID. NO. 25.
  • the one or more risk variants are selected from the group consisting of SEQ. ID. NO.: 26, SEQ. ID. NO.: 27, SEQ. ID. NO.: 28, SEQ. ID. NO.: 29, and SEQ. ID. NO.: 30.
  • the MCRI associated conditions are selected from the group consisting of hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and/or polycystic ovary syndrome.
  • MCRI metabolic clearance rate of insulin
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent, slow down and/or lessen the disease even if the treatment is ultimately unsuccessful.
  • Those in need of treatment include those already with metabolic disorders characterized by abnormal insulin levels, as well as those prone to have metabolic disorders characterized by abnormal insulin levels, or those in whom metabolic disorders characterized by abnormal insulin levels is to be prevented.
  • a therapeutic agent can normalize the metabolic clearance rate of insulin, thereby providing normal levels of insulin in a subject.
  • Metabolic disorders characterized by abnormal insulin levels can include, but are not limited to hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and polycystic ovary syndrome.
  • diagnosis refers to determining the nature or the identity of a condition or disease. A diagnosis may be accompanied by a determination as to the severity of the disease. Diagnosis as it relates to the present invention, relates to the diagnosis of metabolic disorders characterized by abnormal insulin levels. As used herein, “prognostic” or “prognosis” refers to predicting the probable course and outcome of metabolic disorders characterized by abnormal insulin levels. The prognosis can include the presence, the outcome, or the aggressiveness of the disease.
  • biological sample means any biological material obtained from an individual from which nucleic acid molecules can be prepared.
  • examples of a biological sample include, but are not limited to whole blood, plasma, serum, saliva, cheek swab, urine, stool, or other bodily fluid or tissue that contains nucleic acid.
  • Homology refers to the percentage number of nucleic or amino acids that are identical or constitute conservative substitutions. Homology may be determined using sequence comparison programs such as GAP (Deveraux et al, 1984, Nucleic Acids Research 12, 387-395) which is incorporated herein by reference. In this way sequences of a similar or substantially different length to those cited herein could be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP.
  • gene is meant a unit of inheritance that occupies a specific locus on a chromosome and consists of transcriptional and/or translational regulatory sequences and/or a coding region and/or non-translated sequences (i.e., introns, 5' and 3' translated sequences).
  • locus generally refers to a genetically defined region of a chromosome carrying a gene or any other characterized sequence.
  • Suitable mammals that fall within the scope of the invention include, but are not restricted to, primates, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes).
  • livestock animals e.g., sheep, cows, horses, donkeys, pigs
  • laboratory test animals e.g., rabbits, mice, rats, guinea pigs, hamsters
  • companion animals e.g., cats, dogs
  • captive wild animals e.g., foxes, deer, dingoes.
  • biological sample means any biological material obtained from an individual from which nucleic acid molecules can be prepared.
  • examples of a biological sample include, but are not limited to whole blood, plasma, serum, saliva, cheek swab, urine, stool, or other bodily fluid or tissue that contains nucleic acid.
  • polymorphism refers to a difference in the nucleotide or amino acid sequence of a given region as compared to a nucleotide or amino acid sequence in a homologous-region of another individual, in particular, a difference in the nucleotide of amino acid sequence of a given region which differs between individuals of the same species.
  • a polymorphism is generally defined in relation to a reference sequence.
  • Polymorphisms include single nucleotide differences, differences in sequence of more than one nucleotide, and single or multiple nucleotide insertions, inversions and deletions; as well as single amino acid differences, differences in sequence of more than one amino acid, and single or multiple amino acid insertions, inversions, and deletions.
  • a "polymorphic site" is the locus at which the variation occurs. It shall be understood that where a polymorphism is present in a nucleic acid sequence, and reference is made to the presence of a particular base or bases at a polymorphic site, the present invention encompasses the complementary base or bases on the complementary strand at that site.
  • polynucleotide or “nucleic acid” as used herein designates mRNA, RNA, cRNA, cDNA or DNA.
  • the term typically refers to oligonucleotides greater than 30 nucleotide residues in length.
  • Polypeptide “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. Thus, these terms apply to amino acid polymers in which one or more amino acid residues is a synthetic non- naturally occurring amino acid, such as a chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally-occurring amino acid polymers.
  • single nucleotide polymorphism refers to a change in which a single base in the DNA differs (such as via substitutions, addition or deletion) from the usual base at that position.
  • a single nucleotide polymorphism is characterized by the presence in a population of one or two, three or four nucleotides (i.e., adenosine, cytosine, guanosine or thymidine) at a particular locus in a genome such as the human genome.
  • rs2554389, rs4843155, rsl 1259917, rs765524, rs9920704, rsl 1638600, rsl2898206, rs7175914, and rs4297647 examples of which are described herein as SEQ. ID. NO.: 1 , SEQ. ID. NO.: 2, SEQ. ID. NO.: 3, SEQ. ID. NO.: 4, SEQ. ID. NO.: 5, SEQ. ID. NO.: 6, SEQ. ID. NO.: 7, SEQ. ID. NO.: 8, and SEQ. ID. NO.: 9, respectively.
  • genetic variants at the CMIP genetic locus are provided as rs3803655, rs2927299, rsl2597836, rsl 1862343, rs9926618, rsl 1865203, rs2925980, rsl2599865, rsl6955523, rs291 1276, rs2966079, rs2317240, rs7192108, rsl0514517, rs4889332, and rsl 1 150398, examples of which are described herein as SEQ. ID. NO.: 10, SEQ. ID. NO. 11 , SEQ. ID. NO.: 12, SEQ. ID. NO.: 13, SEQ. ID.
  • SEQ. ID. NO.: 14 SEQ. ID. NO.: 15, SEQ. ID. NO.: 16, SEQ. ID. NO.: 17, SEQ. ID. NO.: 18, SEQ. ID. NO.: 19, SEQ. ID. NO.: 20, SEQ. ID. NO.: 21, SEQ. ID. NO.: 22, SEQ. ID. NO.: 23, SEQ. ID. NO.: 24, and SEQ. ID. NO. 25, respectively.
  • examples of genetic variants rs7642040, rs2034860, rs7596457, rs2068061 , and rs4803676 are described herein as SEQ. ID. NO.: 26, SEQ. ID. NO.: 27, SEQ. ID. NO.: 28, SEQ. ID. NO.: 29, and SEQ. ID. NO.: 30, respectively.
  • the inventors conducted a pilot genome -wide association study (GWAS) in subjects from the Mexican-American Hypertension-Insulin Resistance (HTN-IR) cohort, all of whom had undergone euglycemic hyperinsulinemic clamps.
  • the GWAS identified 88 single nucleotide polymorphisms (SNPs) associated with MCRI.
  • SNPs single nucleotide polymorphisms
  • Four intergenic SNPs reached genome- wide significance. Replication was evaluated by examining the HTN-IR subjects who were not part of the initial GWAS. Eight of the 88 GWAS SNPs replicated were associated with MCRI.
  • Other SNPs associated with MCRI were found in the ADAMTSL3 and CMIP genes. This is among the first GWAS in MCRI, and has shed new light into the genetic control of this poorly-understood trait critical to metabolic disorders.
  • the present invention provides a method of prognosing an abnormal MCRI and/or associated conditions in an individual by determining the presence or absence of one or more MCRI genetic risk variants, where the presence of one or more MCRI genetic risk variants is indicative of abnormal MCRI and/or associated conditions.
  • the MCRI associated conditions include one or more metabolic disorders characterized by abnormal insulin levels relative to a healthy subject.
  • the MCRI associated conditions can include, but are not limited to hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and polycystic ovary syndrome.
  • the one or more MCRI genetic risk variants are at the genetic loci of ADAMTSL3 and/or CMIP.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of ADAMTSL3 can include, but are not limited to rs2554389, rs4843155, rsl 1259917, rs765524, rs9920704, rsl 1638600, rsl2898206, rs7175914, and rs4297647.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of CMIP can include, but are not limited to rs3803655, rs2927299, rsl2597836, rsl 1862343, rs9926618, rsl 1865203, rs2925980, rsl2599865, rsl6955523, rs2911276, rs2966079, rs2317240, rs7192108, rsl0514517, rs4889332, and rsl 1150398.
  • the present invention provides a method of diagnosing susceptibility to an abnormal MCRI and/or associated conditions in an individual by determining the presence or absence of one or more MCRI genetic risk variants, where the presence of one or more MCRI genetic risk variants is indicative of susceptibility to an abnormal MCRI and/or associated conditions.
  • the MCRI associated conditions include one or more metabolic disorders characterized by abnormal insulin levels relative to a healthy subject.
  • the MCRI associated conditions can include, but are not limited to hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and polycystic ovary syndrome.
  • the one or more MCRI genetic risk variants are at the genetic loci of ADAMTSL3 and/or CMIP.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of ADAMTSL3 can include, but are not limited to rs2554389, rs4843155, rsl 1259917, rs765524, rs9920704, rsl 1638600, rsl2898206, rs7175914, and rs4297647.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of CMIP can include, but are not limited to rs3803655, rs2927299, rsl2597836, rsl 1862343, rs9926618, rsl 1865203, rs2925980, rsl2599865, rsl6955523, rs2911276, rs2966079, rs2317240, rs7192108, rsl0514517, rs4889332, and rsl 1150398.
  • the present invention provides a method of diagnosing an abnormal MCRI and/or associated conditions in an individual by determining the presence or absence of one or more MCRI genetic risk variants, where the presence of one or more MCRI genetic risk variants is indicative of MCRI and/or associated conditions.
  • the MCRI associated conditions can include one or more metabolic disorders characterized by abnormal insulin levels relative to a healthy subject.
  • the MCRI associated conditions can include, but are not limited to hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and polycystic ovary syndrome.
  • the one or more MCRI genetic risk variants are at the genetic loci of ADAMTSL3 and/or CMIP.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of ADAMTSL3 can include, but are not limited to rs2554389, rs4843155, rsl 1259917, rs765524, rs9920704, rsl 1638600, rsl2898206, rs7175914, and rs4297647.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of CMIP can include, but are not limited to rs3803655, rs2927299, rsl2597836, rsl 1862343, rs9926618, rsl 1865203, rs2925980, rsl2599865, rsl6955523, rs291 1276, rs2966079, rs2317240, rs7192108, rsl0514517, rs4889332, and rsl 1150398.
  • the present invention provides a method of treating an individual for abnormal MCRI and/or associated conditions by determining the presence of one or more MCRI genetic risk variants, and treating the individual.
  • the MCRI associated conditions include one or more metabolic disorders characterized by abnormal insulin levels relative to a healthy subject.
  • the MCRI associated conditions include, but are not limited to hypertension-insulin resistance, atherosclerosis, obesity, metabolic syndrome, fatty liver, and polycystic ovary syndrome.
  • the one or more MCRI genetic risk variants are at the genetic loci of ADAMTSL3 and/or CMIP.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of ADAMTSL3 can include, but are not limited to rs2554389, rs4843155, rsl 1259917, rs765524, rs9920704, rsl 1638600, rsl2898206, rs7175914, and rs4297647.
  • Examples of the one or more MCRI genetic risk variants at the genetic loci of CMIP can include, but are not limited to rs3803655, rs2927299, rsl2597836, rsl 1862343, rs9926618, rsl 1865203, rs2925980, rsl2599865, rsl6955523, rs2911276, rs2966079, rs2317240, rs7192108, rsl0514517, rs4889332, and rsl 1150398.
  • a variety of methods can be used to determine the presence or absence of a variant allele or haplotype.
  • enzymatic amplification of nucleic acid from an individual may be used to obtain nucleic acid for subsequent analysis.
  • the presence or absence of a variant allele or haplotype may also be determined directly from the individual's nucleic acid without enzymatic amplification.
  • nucleic acid means a polynucleotide such as a single or double-stranded DNA or R A molecule including, for example, genomic DNA, cDNA and mRNA.
  • nucleic acid encompasses nucleic acid molecules of both natural and synthetic origin as well as molecules of linear, circular or branched configuration representing either the sense or antisense strand, or both, of a native nucleic acid molecule.
  • the presence or absence of a variant allele or haplotype may involve amplification of an individual's nucleic acid by the polymerase chain reaction.
  • Use of the polymerase chain reaction for the amplification of nucleic acids is well known in the art (see, for example, Mullis et al. (Eds.), The Polymerase Chain Reaction, Birkhauser, Boston, (1994)).
  • a TaqmanB allelic discrimination assay available from Applied Biosystems may be useful for determining the presence or absence of a variant allele. In a TaqmanB allelic discrimination assay, a specific, fluorescent, dye-labeled probe for each allele is constructed.
  • the probes contain different fluorescent reporter dyes such as FAM and VICTM to differentiate the amplification of each allele.
  • each probe has a quencher dye at one end which quenches fluorescence by fluorescence resonant energy transfer (FRET).
  • FRET fluorescence resonant energy transfer
  • each probe anneals specifically to complementary sequences in the nucleic acid from the individual.
  • the 5' nuclease activity of Taq polymerase is used to cleave only probe that hybridize to the allele. Cleavage separates the reporter dye from the quencher dye, resulting in increased fluorescence by the reporter dye.
  • the fluorescence signal generated by PCR amplification indicates which alleles are present in the sample.
  • Minor grove binder include, but are not limited to, compounds such as dihydrocyclopyrroloindole tripeptide (DPI,).
  • Sequence analysis also may also be useful for determining the presence or absence of a variant allele or haplotype.
  • Restriction fragment length polymorphism (RFLP) analysis may also be useful for determining the presence or absence of a particular allele (Jarcho et al. in Dracopoli et al., Current Protocols in Human Genetics pages 2.7.1-2.7.5, John Wiley & Sons, New York; Innis et al.,(Ed.), PCR Protocols, San Diego: Academic Press, Inc. (1990)).
  • restriction fragment length polymorphism analysis is any method for distinguishing genetic polymorphisms using a restriction enzyme, which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat.
  • a restriction enzyme which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat.
  • RFLP analysis depends upon an enzyme that can differentiate two alleles at a polymorphic site.
  • Allele-speciflc oligonucleotide hybridization may also be used to detect a disease- predisposing allele. Allele-speciflc oligonucleotide hybridization is based on the use of a labeled oligonucleotide probe having a sequence perfectly complementary, for example, to the sequence encompassing a disease-predisposing allele. Under appropriate conditions, the allele-specific probe hybridizes to a nucleic acid containing the disease-predisposing allele but does not hybridize to the one or more other alleles, which have one or more nucleotide mismatches as compared to the probe.
  • a second allele-specific oligonucleotide probe that matches an alternate allele also can be used.
  • the technique of allele-specific oligonucleotide amplification can be used to selectively amplify, for example, a disease-predisposing allele by using an allele-specific oligonucleotide primer that is perfectly complementary to the nucleotide sequence of the disease-predisposing allele but which has one or more mismatches as compared to other alleles (Mullis et al., supra, (1994)).
  • the one or more nucleotide mismatches that distinguish between the disease-predisposing allele and one or more other alleles are preferably located in the center of an allele-specific oligonucleotide primer to be used in allele-specific oligonucleotide hybridization.
  • an allele-specific oligonucleotide primer to be used in PCR amplification preferably contains the one or more nucleotide mismatches that distinguish between the disease-associated and other alleles at the 3' end of the primer.
  • a heteroduplex mobility assay is another well known assay that may be used to detect a SNP or a haplotype. HMA is useful for detecting the presence of a polymorphic sequence since a DNA duplex carrying a mismatch has reduced mobility in a polyacrylamide gel compared to the mobility of a perfectly base-paired duplex (Delwart et al., Science 262: 1257- 1261 (1993); White et al, Genomics 12:301-306 (1992)).
  • SSCP single strand conformational, polymorphism
  • This technique can be used to detect mutations based on differences in the secondary structure of single-strand DNA that produce an altered electrophoretic mobility upon non-denaturing gel electrophoresis. Polymorphic fragments are detected by comparison of the electrophoretic pattern of the test fragment to corresponding standard fragments containing known alleles.
  • Denaturing gradient gel electrophoresis also may be used to detect a SNP and/or a haplotype.
  • DGGE Denaturing gradient gel electrophoresis
  • double-stranded DNA is electrophoresed in a gel containing an increasing concentration of denaturant; double- stranded fragments made up of mismatched alleles have segments that melt more rapidly, causing such fragments to migrate differently as compared to perfectly complementary sequences (Sheffield et al., "Identifying DNA Polymorphisms by Denaturing Gradient Gel Electrophoresis” in Innis et al., supra, 1990).
  • Illustrative of optical methods in addition to microscopy, both confocal and non-confocal, are detection of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, and birefringence or refractive index (e.g., surface plasmon resonance, ellipsometry, a resonant mirror method, a grating coupler waveguide method or inter ferometry).
  • detection of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, and birefringence or refractive index e.g., surface plasmon resonance, ellipsometry, a resonant mirror method, a grating coupler waveguide method or inter ferometry.
  • biomarker may be captured using biospecific capture reagents, such as antibodies, aptamers or antibodies that recognize the biomarker and modified forms of it. This method could also result in the capture of protein interactors that are bound to the proteins or that are otherwise recognized by antibodies and that, themselves, can be biomarkers.
  • the biospecific capture reagents may also be bound to a solid phase. Then, the captured proteins can be detected by SELDI mass spectrometry or by eluting the proteins from the capture reagent and detecting the eluted proteins by traditional MALDI or by SELDI.
  • SELDI affinity capture mass spectrometry
  • SEAC Surface-Enhanced Affinity Capture
  • mass spectrometers are time-of-flight, magnetic sector, quadrupole filter, ion trap, ion cyclotron resonance, electrostatic sector analyzer and hybrids of these.
  • the presence of biomarkers such as polypeptides maybe detected using traditional immunoassay techniques.
  • Immunoassay requires biospecific capture reagents, such as antibodies, to capture the analytes.
  • the assay may also be designed to specifically distinguish protein and modified forms of protein, which can be done by employing a sandwich assay in which one antibody captures more than one form and second, distinctly labeled antibodies, specifically bind, and provide distinct detection of, the various forms.
  • Antibodies can be produced by immunizing animals with the biomolecules.
  • Traditional immunoassays may also include sandwich immunoassays including ELISA or fluorescence- based immunoassays, as well as other enzyme immunoassays.
  • biomarkers Prior to detection, biomarkers may also be fractionated to isolate them from other components in a solution or of blood that may interfere with detection. Fractionation may include platelet isolation from other blood components, sub-cellular fractionation of platelet components and/or fractionation of the desired biomarkers from other biomolecules found in platelets using techniques such as chromatography, affinity purification, ID and 2D mapping, and other methodologies for purification known to those of skill in the art.
  • a sample is analyzed by means of a biochip.
  • Biochips generally comprise solid substrates and have a generally planar surface, to which a capture reagent (also called an adsorbent or affinity reagent) is attached. Frequently, the surface of a biochip comprises a plurality of addressable locations, each of which has the capture reagent bound there.
  • MCRI metabolic clearance rate
  • the inventors conducted a pilot genome-wide association study (GWAS) in 310 subjects from the Mexican-American Hypertension-Insulin Resistance (HTN-IR) cohort, all of whom had undergone euglycemic hyperinsulinemic clamps.
  • the GWAS identified 88 single nucleotide polymorphisms associated with MCRI at P ⁇ 1 x 10 " 5 (figure 1).
  • Four intergenic SNPs reached genome -wide significance (P ⁇ 5 x 10 "8 ) (figure 1, the first 4 SNPs).
  • ADAMTSL3 is highly expressed in the liver, kidney, heart, and skeletal muscle, which are key insulin-clearing tissues.
  • a different ADAMTSL3 SNP has been associated with height in GWAS studies (Weedon MN et al., Nat Genet 2008;40:75-83); as insulin is a growth factor, an effect of this gene on both MCRI and height is plausible.
  • Another of the GWAS SNP associations that replicated in the remaining HTN-IR cohort is located in the CMIP gene. Fifteen additional SNPs in CMIP that were included in the iSelect also demonstrated association with MCRI in the entire cohort (figure 4).
  • CMIP interacts with filamin A and inhibits NF-KB activity, suggesting possible involvement in MCRI via cytoskeletal organization and/or modulation of inflammation. This is among the first GWAS in MCRI, and has shed new light into the genetic control of this poorly-understood trait critical to metabolic disorders.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Analytical Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne des procédés de détermination d'une clairance métabolique anormale de l'insuline et/ou d'affections associées chez un patient. Dans un mode de réalisation, les méthodes permettent de déterminer qu'il y a clairance anormale de l'insuline et/ou une affection associée grâce à la détermination de la présence ou pas d'un ou plusieurs variants du risque génétique de la clairance métabolique anormale de l'insuline au niveau du locus génétique ADAMTSL3 et/ou CMIP.
PCT/US2011/028902 2010-03-17 2011-03-17 Méthodes de diagnostic et de traitement d'affections associées à la clairance métabolique de l'insuline Ceased WO2011116244A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31491610P 2010-03-17 2010-03-17
US61/314,916 2010-03-17

Publications (2)

Publication Number Publication Date
WO2011116244A2 true WO2011116244A2 (fr) 2011-09-22
WO2011116244A3 WO2011116244A3 (fr) 2011-12-29

Family

ID=44649839

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/028902 Ceased WO2011116244A2 (fr) 2010-03-17 2011-03-17 Méthodes de diagnostic et de traitement d'affections associées à la clairance métabolique de l'insuline

Country Status (1)

Country Link
WO (1) WO2011116244A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8178294B2 (en) 2002-06-14 2012-05-15 Cedars-Sinai Medical Center Method of haplotype-based genetic analysis for determining risk for developing insulin resistance, coronary artery disease and other phenotypes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068664A2 (fr) * 2004-01-09 2005-07-28 The Regents Of The University Of California Modele d'expression genique specifiques d'un type de cellule
EP1773860A4 (fr) * 2004-07-22 2009-05-06 Sequenom Inc Méthodes d'évaluation du risque d"apparition de diabètes de type ii et traitements associés
WO2006084699A1 (fr) * 2005-02-11 2006-08-17 Roche Diagnostics Gmbh Nouveau marqueur de methylation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8178294B2 (en) 2002-06-14 2012-05-15 Cedars-Sinai Medical Center Method of haplotype-based genetic analysis for determining risk for developing insulin resistance, coronary artery disease and other phenotypes

Also Published As

Publication number Publication date
WO2011116244A3 (fr) 2011-12-29

Similar Documents

Publication Publication Date Title
Volpi et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia
EP2689036B1 (fr) Méthodes de diagnostic et de traitement des granulomes intestinaux et de la faible densité osseuse dans la maladie intestinale inflammatoire
US20110189685A1 (en) Methods of using jak3 genetic variants to diagnose and predict crohn's disease
US20190203295A1 (en) Methods of predicting complication and surgery in crohn's disease
JP5759500B2 (ja) 緑内障進行リスクの判定方法
US20100184050A1 (en) Diagnosis and treatment of inflammatory bowel disease in the puerto rican population
WO2009052512A2 (fr) Procédés d'utilisation de variants génétiques pour diagnostiquer et prévenir la maladie inflammatoire de l'intestin
WO2008137762A2 (fr) Procédés de diagnostic et de traitement de la maladie de crohn
WO2010039931A2 (fr) Procédés d’utilisation de gènes de la voie il17rd et il23-il17 pour diagnostiquer la maladie de crohn
WO2008141148A2 (fr) Caractérisation de la réponse à l'antigène cbir1 pour le diagnostic et le traitement de la maladie de crohn
WO2011017120A1 (fr) Utilisation de variants des voies ccr9, ccl25, batf et il17/il23 pour diagnostiquer et traiter l'affection abdominale inflammatoire
US20130012604A1 (en) Methods of using prdm1 genetic variants to prognose, diagnose and treat inflammatory bowel disease
McKnight et al. Resequencing of genes for transforming growth factor β1 (TGFB1) type 1 and 2 receptors (TGFBR1, TGFBR2), and association analysis of variants with diabetic nephropathy
WO2009144480A1 (fr) Traitement et diagnostic de troubles comportementaux
US9305137B1 (en) Methods of identifying the genetic basis of a disease by a combinatorial genomics approach, biological pathway approach, and sequential approach
US20120088245A1 (en) Methods of diagnosing insulin resistance and sensitivity
US20230203574A1 (en) Blood dna methylation biomarker diagnostic test for anxiety and depressive disorders
JP2008545390A (ja) 遺伝的多型を用いた肺癌を発達させるリスクの評価方法
WO2010075584A1 (fr) Méthodes de diagnostic et de prévision de la maladie de crohn à partir de profils hygiéniques et sérologiques pédiatriques
WO2010083234A1 (fr) Procédés d'utilisation de variantes génétiques smad3 et jak2 pour diagnostiquer et prévoir une maladie intestinale inflammatoire
WO2011116244A2 (fr) Méthodes de diagnostic et de traitement d'affections associées à la clairance métabolique de l'insuline
US20130281319A1 (en) Methods and compositions for assessment of pulmonary function and disorders
WO2009055596A2 (fr) Procédés d'utilisation de variants génétiques permettant de diagnostiquer et de prédire un syndrome métabolique et des traits associés
AU2007231141B2 (en) Hereditary cataract status in canines based on HSF4 gene marker
Balabas et al. Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11757031

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11757031

Country of ref document: EP

Kind code of ref document: A2