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WO2015168699A1 - Procédés de prédiction d'une colite ulcéreuse réfractaire au traitement médical (curm) nécessitant une colectomie - Google Patents

Procédés de prédiction d'une colite ulcéreuse réfractaire au traitement médical (curm) nécessitant une colectomie Download PDF

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WO2015168699A1
WO2015168699A1 PCT/US2015/029101 US2015029101W WO2015168699A1 WO 2015168699 A1 WO2015168699 A1 WO 2015168699A1 US 2015029101 W US2015029101 W US 2015029101W WO 2015168699 A1 WO2015168699 A1 WO 2015168699A1
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Prior art keywords
mruc
genetic risk
colectomy
risk
genetic
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Inventor
Dermot MCGOVERN
Talin Haritunians
Stephan Targan
Philip FLESHNER
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Cedars Sinai Medical Center
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Cedars Sinai Medical Center
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Priority to EP15785256.7A priority Critical patent/EP3137628A4/fr
Priority to CA2946317A priority patent/CA2946317A1/fr
Publication of WO2015168699A1 publication Critical patent/WO2015168699A1/fr
Priority to US15/338,782 priority patent/US20170044615A1/en
Anticipated expiration legal-status Critical
Priority to US16/366,894 priority patent/US20190218616A1/en
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    • 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
    • C12Q2600/112—Disease subtyping, staging or classification
    • 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 the fields of genetics and inflammatory disease, specifically medically refractive-UC (mrUC).
  • mrUC medically refractive-UC
  • CD Crohn's disease
  • UC ulcerative colitis
  • IBD idiopathic inflammatory bowel disease
  • CD and UC are thought to be related disorders that share some genetic susceptibility loci but differ at others.
  • Various embodiments of the present invention provide for a method of determining the need for colectomy in a subject with mrUC comprising: obtaining a sample from the subject; assaying the sample to detect the presence or absence of mrUC genetic risk variants, wherein the mrUC genetic risk variants are selected from the group consisting of SEQ ID NOs: 1-99; calculating a genetic risk score based on the detection of the mrUC genetic risk variants; determining that the subject has an increased likelihood of needing colectomy if the calculated genetic risk score is at the high end of the observed range and determining that the subject has a decreased likelihood of needing colectomy if the calculated genetic risk score is at the low end of the observed range.
  • the genetic risk score is obtained by calculating a total number of risk alleles for all the mrUC genetic risk variants assayed, wherein the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2.
  • Various other embodiments further comprise obtaining a theoretical range and an observed range based on the genetic risk score, wherein the theoretical range consists of the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed and wherein the observed range consists of the actual minimum and maximum number of risk alleles detected.
  • the number of mrUC genetic risk variants assayed is 46
  • the theoretical range is 0-92 and the observed range is 28-60.
  • the number of mrUC genetic risk variants assayed is 36
  • the theoretical range is 0-72 and the observed range is 16-38.
  • Various other embodiments further comprise prescribing colectomy to subjects having a genetic risk score at the high end of the observed range.
  • time to colectomy is lower in a subject with a genetic risk score at the high end of the observed range and time to colectomy is higher in a subject with a genetic risk score at the low end of the observed range.
  • the time to colectomy is 10 to 70 months from detection.
  • Various embodiments of the present invention provide for a method of diagnosing susceptibility to mrUC in a subject, comprising: obtaining a sample from the subject; assaying the sample to detect the presence or absence of mrUC genetic risk variants, wherein the mrUC genetic risk variants are selected from the group consisting of SEQ ID NOs: 1-99; calculating a genetic risk score based on the detection of the mrUC genetic risk variants; and diagnosing susceptibility to mrUC based on the calculated risk score, wherein a subject has an increased susceptibility to mrUC if the calculated genetic risk score is at the high end of the observed range and a subject has a decreased susceptibility to mrUC if the calculated genetic risk score is at the low end of the observed range.
  • the genetic risk score is obtained by calculating a total number of risk alleles for all the mrUC genetic risk variants assayed, wherein the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2.
  • Various other embodiments further comprise obtaining a theoretical range and an observed range based on the genetic risk score, wherein the theoretical range consists of the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed and wherein the observed range consists of the actual minimum and maximum number of risk alleles detected.
  • an increase in the number of risk alleles detected signifies an increase in susceptibility to mrUC.
  • the number of mrUC genetic risk variants assayed is 46
  • the theoretical range is 0-92 and the observed range is 28-60.
  • the number of mrUC genetic risk variants assayed is 36
  • the theoretical range is 0-72 and the observed range is 16-38.
  • Various other embodiments further comprise prescribing colectomy to subjects diagnosed with a susceptibility for mrUC and have a genetic risk score at the high end of the observed range.
  • the time to colectomy is lower in a subject with a genetic risk score at the high end of the observed range and the time to colectomy is higher in a subject with a genetic risk score at the low end of the observed range.
  • the time to colectomy is 10 to 70 months from detection.
  • a method of treating mrUC in a subject comprising: obtaining a sample from the subject; assaying the sample to detect the presence or absence of mrUC genetic risk variants, wherein the mrUC genetic risk variants are selected from the group consisting of SEQ ID NOs: 1-99; calculating a genetic risk score based on the detection of the mrUC genetic risk variants; diagnosing susceptibility to mrUC based on the calculated risk score, wherein a subject has an increased susceptibility to mrUC if the calculated genetic risk score is high and a subject has a decreased susceptibility to mrUC if the calculated genetic risk score is low; and prescribing colectomy to the subject with an increased susceptibility to mrUC.
  • the genetic risk score is obtained by calculating a total number of risk alleles for all the mrUC genetic risk variants assayed, wherein the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2.
  • Various other embodiments further comprise obtaining a theoretical range and an observed range based on the genetic risk score, wherein the theoretical range consists of the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed and wherein the observed range consists of the actual minimum and maximum number of risk alleles detected.
  • an increase in the number of risk alleles detected signifies an increase in susceptibility to mrUC.
  • the number of mrUC genetic risk variants assayed is 46
  • the theoretical range is 0-92 and the observed range is 28-60.
  • the number of mrUC genetic risk variants assayed is 36
  • the theoretical range is 0-72 and the observed range is 16-38.
  • the treatment is colectomy and is prescribed to subjects diagnosed with a susceptibility for mrUC and have a genetic risk score at the high end of the observed range.
  • the time to colectomy is lower in a subject with a genetic risk score at the high end of the observed range and the time to colectomy is higher in a subject with a genetic risk score at the low end of the observed range.
  • the time to colectomy is 10 to 70 months from detection.
  • kits for prognostic use comprising: a single prognostic panel comprising one or more medically refractive ulcerative colitis (mrUC) genetic risk variants described in SEQ ID NOs: 1-99.
  • mrUC medically refractive ulcerative colitis
  • Figure 1 depicts, in accordance with an embodiment herein, a schematic describing mrUC vs. non-mrUC survival analysis and risk modeling.
  • Figure 2 depicts, in accordance with an embodiment herein,
  • A) Higher risk score categories are associated with mrUC ( ⁇ 2 test for trend p ⁇ 2.2x10-16). Risk score (observed range: 28-60) was divided into quarters: scores 28-38 (risk-A); scores 39-45 (risk-B); scores 46-52 (risk-C); and scores 53-60 (risk-D). Percentage of mrUC is noted, along with the total number of UC subjects in each risk category.
  • B) Higher risk score categories are associated with an earlier progression to colectomy at 24 and 60 months. Risk score was divided into quarters: scores 28-38 (risk-A); scores 39-45 (risk-B); scores 46-52 (risk-C); and scores 53-60 (risk-D).
  • risk of colectomy was 3.1%, 19.1%o and 62% for risk-B, -C, and -D, respectively.
  • Risk of colectomy at 60 months increased to 8.3%, 48.4%, 84% for risk-B, -C, and -D, respectively.
  • Total number of UC subjects in each risk category is given.
  • Figure 3 depicts, in accordance with an embodiment herein, serology data demonstrating an association of mrUC with Cbirl, ASCA, OmpC and 12 antibody quartile sum in mrUC and non-mrUC subjects.
  • Figure 4 depicts, in accordance with an embodiment herein, single SNP association tested with logistic regression analysis in mrUC and non-mrUC subjects.
  • Figure 5 depicts, in accordance with an embodiment herein, a schematic describing mr UC vs. Non-mrUC survival analysis and risk modeling for mrUC.
  • Figure 6 depicts, in accordance with an embodiment herein, a chart with the top 36 associated SNPs from Analysis I and II, referenced herein.
  • Figure 7 depicts, in accordance with an embodiment herein, higher risk score association with mrUC.
  • Figure 8 depicts, in accordance with an embodiment herein, higher risk score association with earlier progression to colectomy.
  • Figure 9 depicts, in accordance with an embodiment herein, higher risk score exhibits a shorter overall median time to colectomy.
  • Figure 10 depicts, in accordance with an embodiment herein, potential clinical utility of the association of a higher risk score with earlier progression to colectomy.
  • FIG 11 depicts, in accordance with an embodiment herein, role for major histocompatibility (MHC) in UC severity in mrUC versus controls.
  • MHC major histocompatibility
  • Figure 12 depicts, in accordance with an embodiment herein, single SNP association tested with regression analysis in mrUC versus controls. DESCRIPTION OF THE INVENTION
  • IBD as used herein is an abbreviation of inflammatory bowel disease.
  • CD Crohn's Disease
  • GWAS as used herein is an abbreviation of genome wide association study.
  • mrUC ulcerative colitis with symptoms uncontrolled by medical therapy. Also referred to as mr-UC.
  • mrUC genetic risk variant refers to genetic variants, or SNPs, that have an association with the mrUC, or ulcerative colitis requiring colectomy, phenotype.
  • biological sample means any biological material from which nucleic acid molecules can be prepared.
  • material encompasses whole blood, plasma, saliva, cheek swab, or other bodily fluid or tissue that contains nucleic acid.
  • a "Risk Score” as used herein is a calculated number, obtained by adding/totaling the total number of risk alleles for all the mrUC genetic risk variants assayed.
  • the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2.
  • the risk score based on analyzed mrUC genetic risk variants, is calculated in other patients and the cumulative risk scores for all patients analyzed provide an observed range as discussed below.
  • “Risk Group” refers to a subset of patients who fall within the same category for colectomy risk based on the detected mrUC risk variants in the subject's biological sample.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition, prevent the pathologic condition, pursue or obtain good overall survival, or lower the chances of the individual developing the condition even if the treatment is ultimately unsuccessful.
  • Those in need of treatment include those already with the condition as well as those prone to have the condition or those in whom the condition is to be prevented.
  • Examples of mrUC treatment include, but are not limited to, active surveillance, observation, surgical intervention (such as colectomy), drug therapy (anti-inflammatory and/or immune system suppressor drugs), targeted therapy to genes known to be involved in mrUC, such as, but not limited to those referenced herein and/or a combination thereof.
  • Time to colectomy refers to the amount of time between the determination that a subject had an increased likelihood of needing colectomy and actually undergoing colectomy.
  • the subject has a reduced time to colectomy (for example: 0-6 months, 6 months - 1 year, 1 - 2 years or 2-3 years) if the subject has a high risk score.
  • the subject has an increased time to colectomy (for example, 3-4 years, 4-5 years or more) if the subject has a low risk score.
  • Theoretical range refers to the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed. For example, if 46 genetic risk variants are analyzed, the theoretical range is 0-92, where 0 is the minimum number of risk alleles and 92 (46 x 2 alleles) is the maximum number of risk alleles.
  • Observed range refers to the minimum and maximum risk score, which is based on the risk alleles detected for the patient cohort, as described above. For example, an observed range of 28-60, obtained when analyzing the 46 genetic risk variants, results in a minimum of 28 and a maximum of 60. "High end” of an observed range as used herein refers to a genetic risk score that is within for example, 10 - 15 points of the maximum observed range.
  • Low end of an observed range refers to a genetic score that is within for example, 10 - 15 points of the minimum observed range.
  • UC Acute severe ulcerative colitis
  • mrUC medically refractory UC
  • the inventors used a genome-wide association study (GWAS) in a well characterized cohort of UC patients to identify genetic variation that contributes to mrUC.
  • GWAS genome-wide association study
  • a GWAS comparing 324 mrUC patients with 537 Non-mrUC patients was analyzed using logistic regression and Cox proportional hazards methods.
  • the mrUC patients were compared with 2601 healthy controls.
  • a risk score based on the combination of 46 SNPs associated with mrUC explained 48% of the variance for colectomy risk in the cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%> and 100% in the four groups.
  • a SNP -based risk scoring system identified herein by GWAS analyses, can provide a useful adjunct to clinical parameters for predicting natural history in UC. Furthermore, discovery of genetic processes underlying disease severity can help to identify pathways for novel therapeutic intervention in severe UC.
  • Various embodiments of the present invention provide for a method of determining the need for colectomy in a subject with mrUC comprising: obtaining a sample from the subject; assaying the sample to detect the presence or absence of mrUC genetic risk variants, wherein the mrUC genetic risk variants are selected from the group consisting of SEQ ID NOs: 1-99; calculating a genetic risk score based on the detection of the mrUC genetic risk variants; determining that the subject has an increased likelihood of needing colectomy if the calculated genetic risk score is at the high end of the observed range and determining that the subject has a decreased likelihood of needing colectomy if the calculated genetic risk score is at the low end of the observed range.
  • the genetic risk score is obtained by calculating a total number of risk alleles for all the mrUC genetic risk variants assayed, wherein the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2.
  • Various other embodiments further comprise obtaining a theoretical range and an observed range based on the genetic risk score, wherein the theoretical range consists of the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed and wherein the observed range consists of the actual minimum and maximum number of risk alleles detected.
  • the number of mrUC genetic risk variants assayed is 46
  • the theoretical range is 0-92 and the observed range is 28-60.
  • the number of mrUC genetic risk variants assayed is 36
  • the theoretical range is 0-72 and the observed range is 16-38.
  • Various other embodiments further comprise prescribing colectomy to subjects having a genetic risk score at the high end of the observed range.
  • time to colectomy is lower in a subject with a genetic risk score at the high end of the observed range and time to colectomy is higher in a subject with a genetic risk score at the low end of the observed range.
  • the time to colectomy is 10 to 70 months from detection. Diagnosing susceptibility
  • Various embodiments of the present invention provide for a method of diagnosing susceptibility to mrUC in a subject, comprising: obtaining a sample from the subject; assaying the sample to detect the presence or absence of mrUC genetic risk variants, wherein the mrUC genetic risk variants are selected from the group consisting of SEQ ID NOs: 1-99; calculating a genetic risk score based on the detection of the mrUC genetic risk variants; and diagnosing susceptibility to mrUC based on the calculated risk score, wherein a subject has an increased susceptibility to mrUC if the calculated genetic risk score is at the high end of the observed range and a subject has a decreased susceptibility to mrUC if the calculated genetic risk score is at the low end of the observed range.
  • the genetic risk score is obtained by calculating a total number of risk alleles for all the mrUC genetic risk variants assayed, wherein the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2
  • Various other embodiments further comprise obtaining a theoretical range and an observed range based on the genetic risk score, wherein the theoretical range consists of the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed and wherein the observed range consists of the actual minimum and maximum number of risk alleles detected.
  • an increase in the number of risk alleles detected signifies an increase in susceptibility to mrUC.
  • the number of mrUC genetic risk variants assayed is 46
  • the theoretical range is 0-92 and the observed range is 28-60.
  • the number of mrUC genetic risk variants assayed is 36
  • the theoretical range is 0-72 and the observed range is 16-38.
  • Various other embodiments further comprise prescribing colectomy to subjects diagnosed with a susceptibility for mrUC and have a genetic risk score at the high end of the observed range.
  • the time to colectomy is lower in a subject with a genetic risk score at the high end of the observed range and the time to colectomy is higher in a subject with a genetic risk score at the low end of the observed range.
  • the time to colectomy is 10 to 70 months from detection.
  • a method of treating mrUC in a subject comprising: obtaining a sample from the subject; assaying the sample to detect the presence or absence of mrUC genetic risk variants, wherein the mrUC genetic risk variants are selected from the group consisting of SEQ ID NOs: 1-99; calculating a genetic risk score based on the detection of the mrUC genetic risk variants; diagnosing susceptibility to mrUC based on the calculated risk score, wherein a subject has an increased susceptibility to mrUC if the calculated genetic risk score is high and a subject has a decreased susceptibility to mrUC if the calculated genetic risk score is low; and prescribing colectomy to the subject with an increased susceptibility to mrUC.
  • the genetic risk score is obtained by calculating a total number of risk alleles for all the mrUC genetic risk variants assayed, wherein the risk allele for each mrUC genetic risk variant assayed is 0, 1 or 2.
  • Various other embodiments further comprise obtaining a theoretical range and an observed range based on the genetic risk score, wherein the theoretical range consists of the minimum and maximum number of risk alleles possible based on the number of mrUC genetic risk variants assayed and wherein the observed range consists of the actual minimum and maximum number of risk alleles detected.
  • an increase in the number of risk alleles detected signifies an increase in susceptibility to mrUC.
  • the number of mrUC genetic risk variants assayed is 46
  • the theoretical range is 0-92 and the observed range is 28-60.
  • the number of mrUC genetic risk variants assayed is 36
  • the theoretical range is 0-72 and the observed range is 16-38.
  • the treatment is colectomy and is prescribed to subjects diagnosed with a susceptibility for mrUC and have a genetic risk score at the high end of the observed range.
  • the time to colectomy is lower in a subject with a genetic risk score at the high end of the observed range and the time to colectomy is higher in a subject with a genetic risk score at the low end of the observed range.
  • the time to colectomy is 10 to 70 months from detection.
  • Those in need of treatment include those already with the condition as well as those prone to have the condition or those in whom the condition is to be prevented.
  • Examples of mrUC treatment include, but are not limited to, active surveillance, observation, surgical intervention (such as colectomy), drug therapy (anti-inflammatory and/or immune system suppressor drugs), and targeted therapy, directed to genes known to be involved in IBD, such as, but not limited to those referenced herein and/or a combination thereof.
  • Targeted therapy can consist of administering a composition(s) that will modify gene regulation by inhibiting or inducing the target gene expression and/or activity of the gene.
  • kits for prognostic use comprising: a single prognostic panel comprising one or more medically refractive ulcerative colitis (mrUC) genetic risk variants described in SEQ ID NOs: 1-99.
  • mrUC medically refractive ulcerative colitis
  • the present invention is directed to a kit to predict the risk for colectomy, susceptibility to mrUC and/or treatment of mrUC.
  • the kit is useful for practicing the inventive method of determining risk for colectomy in a subject, diagnosing susceptibility to mrUC in a subject and/or treatment of a subject.
  • the kit is an assemblage of materials or components, including at least one of the inventive compositions.
  • the kit contains a composition including a drug that targets genes known to be involved in mrUC, such as the mrUC genetic risk variants, for treatment of mrUC, as described above.
  • the kit contains a composition including primers and probes to genetic risk alleles and/or drugs useful in targeting those genetic risk alleles.
  • kits configured for the purpose of treating mrUC.
  • the kit is configured particularly for the purpose of treating mammalian subjects.
  • the kit is configured particularly for the purpose of treating human subjects.
  • the kit is configured for veterinary applications, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals.
  • kits Instructions for use may be included in the kit. "Instructions for use” typically include a tangible expression describing the technique to be employed in using the components of the kit to effect a desired outcome.
  • the kit also contains other useful components, such as, primers, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.
  • the materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility.
  • the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures.
  • the components are typically contained in suitable packaging material(s).
  • packaging material refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like.
  • the packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment.
  • the term "package” refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components.
  • the packaging material generally has an external label which indicates the contents and/or purpose of the kit and/or its components.
  • a variety of methods can be used to determine the presence or absence of an mrUC genetic risk 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 RNA 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.
  • 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.
  • Mismatches between a probe and allele reduce the efficiency of both probe hybridization and cleavage by Taq polymerase, resulting in little to no fluorescent signal.
  • Improved specificity in allelic discrimination assays can be achieved by conjugating a DNA minor grove binder (MGB) group to a DNA probe as described, for example, in Kutyavin et al., "3 '-minor groove binder-DNA probes increase sequence specificity at PCR extension temperature, "Nucleic Acids Research 28:655-661 (2000)).
  • Minor grove binders 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-specific oligonucleotide hybridization may also be used to detect a disease- predisposing allele. Allele-specific 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. If desired, 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.
  • HMA heteroduplex mobility assay
  • 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).
  • UC Acute severe ulcerative colitis
  • mrUC medically refractory UC
  • the inventors used a genome-wide association study (GWAS) in a well characterized cohort of UC patients to identify genetic variation that contributes to mrUC.
  • GWAS genome-wide association study
  • a GWAS comparing 324 mrUC patients with 537 Non-mrUC patients was analyzed using logistic regression and Cox proportional hazards methods.
  • the mrUC patients were compared with 2601 healthy controls.
  • a risk score based on the combination of 46 SNPs associated with mrUC explained 48% of the variance for colectomy risk in the cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%> and 100%) in the four groups.
  • UC Ulcerative Colitis
  • UC diagnosis was based on standard criteria 31.
  • UC subjects requiring colectomy for severe disease refractory to medical therapies (including intravenous corticosteroids, cyclosporine, and biologic therapies) were classified as medically refractory UC (mrUC).
  • mrUC medically refractory UC
  • time from diagnosis to date of colectomy was collected; time from diagnosis to last follow-up visit was obtained for the Non-mrUC cohort.
  • CHS was approved by the Institutional Review Board at each recruitment site, and subjects provided informed consent for the use of their genetic information. A total of 2,601 Caucasian non-IBD control subjects who underwent GWAS were included in these analyses. African- American CHS participants were excluded from analysis due to insufficient number of ethnically-matched cases.
  • Example 4 Example 4
  • SNPs Single nucleotide polymorphisms
  • mrUC vs. Non-mrUC Survival Analysis and Risk Modeling Single marker association analysis of mrUC vs. Non-mrUC (analysis-I) was performed using a logistic regression model correcting for population stratification using 20 principal components as covariates (PLINK vl .06). Association between medically refractory disease (mrUC) and the top 100 SNPs together (as determined by the lowest corrected p-values) from analysis-I were tested using a stepwise logistic regression model. SNPs were further analyzed by Cox proportional hazards regression utilizing time-to information, as described for UC cases (using the step and glm, and coxph functions, respectively, in R v2.9.0).
  • the 65 SNPs (p ⁇ lxl0-4) from analysis-II are listed herein (Table 2). From these 65 SNPs, 9 SNPs were identified (p ⁇ 3xl0-4) and combined with the 37 SNPs from analysis-I to identify a final risk model consisting of 46 SNPs (see Figure 1 for schematic; Table 3).
  • a genetic risk score was calculated from the total number of risk alleles (0, 1, or 2) across all 46 risk SNPs (theoretical range: 0-92). Risk score (observed range: 28-60) was divided into quarters: scores 28-38 (risk-A); scores 39-45 (risk-B); scores 46-52 (risk-C); and scores 53-60 (risk-D).
  • Receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were calculated using R software v2.9.0, including packages survival and survivalROC 39-41. Sensitivity and specificity curves, positive and negative predictive values, positive (sensitivity/ 1- specificity) and negative likelihood ratio (1- sensitivity/specificity) were all calculated using the R package ROCR 42. 1000-fold replication of 10-fold cross-validation was implemented to validate the fitted logistic regression model. Mean sensitivity and specificity were then re-calculated using the 1000 replicated samples. Bootstrap method with 1000-fold replication was utilized for estimating variability of hazard ratio estimated from the Cox regression model. The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event.
  • Non-IBD Controls Regression Analysis Single marker analysis of genome -wide data for mrUC cases vs.
  • Non-IBD Caucasian controls from CHS analysis-Ill was performed as before, using logistic regression correcting for 20 principal components (PLINK).
  • the inventors performed a GWAS on 324 mrUC and 537 Non-mrUC subjects. Results of this analysis (analysis-I) are given herein and discussed below. Following identification of single markers associated with mrUC, the inventors proceeded to a multivariate approach. Beginning with the top 100 results from analysis-I (p ⁇ 3xl0-4), the inventors performed a stepwise logistic regression and identified 64 SNPs (p ⁇ 0.05) that together were associated with medically refractory disease (mrUC) and were carried forward to survival analysis. Of these 64 SNPs, 37 SNPs remained (Cox proportional hazards regression p ⁇ 0.1; OR 1.2- 1.8), which explained 40% of the variance for mrUC.
  • the inventors further performed a genome-wide Cox proportional hazards regression analysis (analysis-II) on a subset of the UC cohort to identify SNPs involved in earlier progression to colectomy. Testing together the top 65 SNPs from this analysis (p ⁇ lxl0- 4), the inventors identified nine SNPs with Cox proportional hazards p ⁇ 3xl0-4 (individual OR ranged from 1.4-1.6), explaining 17% of the variance. Beginning with the previously identified 37 risk SNP model, these 9 SNPs were added sequentially to the model. This analysis resulted in the final risk model of 46 SNPs (OR for MR- UC for each individual SNP ranged from 1.2-1.9), which explained 48% of the variance for colectomy in the mrUC cohort.
  • analysis-II Cox proportional hazards regression analysis
  • the inventors Based on the genetic risk scores, the inventors grouped the UC cohort into four risk categories; less than 1%> of cases in the lowest risk category (risk- A) were mrUC and the percentage of mrUC increased to ⁇ 17%>, ⁇ 74%> and 100%) in risk-B, -C and -D groups, respectively ( ⁇ 2 test for trend p ⁇ 2.2x10-16; Figure 2A).
  • the median time to colectomy for risk-C and -D categories was 72 months and 23 months, respectively.
  • a score of 44 and 47 can be used to generate a test with a sensitivity (to exclude a diagnosis of colectomy) and specificity (to include a diagnosis) of over 90%>, respectively.
  • Loci corresponding to the 46 SNPs in the risk model include several compelling candidate genes for UC severity and suggest potential biological pathways for further avenues of study.
  • this work supports the paradigm that a group of SNPs, identified by GWAS and combined together may account for a large proportion of the genetic contribution to a complex phenotype (48% of the variance for risk in this study) to provide a risk score with clinical utility.
  • MHC region and TLIA contribute to UC severity.
  • MHC major histocompatibility
  • TNFSF15 TNFSF15
  • the predictive power of diagnostic tests can be evaluated by the area under the curve (AUC), an ROC summary index, which evaluates the probability that one's test correctly identifies a diseased subject from a pair of affected and unaffected individuals.
  • AUC area under the curve
  • ROC summary index evaluates the probability that one's test correctly identifies a diseased subject from a pair of affected and unaffected individuals.
  • a perfect test has an AUC of 1.0, while random chance gives an AUC of 0.5.
  • Screening programs attempting to identify high-risk groups generally have an AUC of -0.80 48.
  • the genetic risk score reported herein yielded an AUC of 0.91.
  • the inventors calculated operating characteristics in an attempt to determine whether a prognostic test based on these genetic data would be clinically useful.
  • the score of 44 and 47 (out of a possible score of 60) can be used to generate a test with a sensitivity and specificity of over 90%, respectively.
  • the fitted model was robust, given the comparable mean sensitivity and specificity following cross-validation.
  • likelihood ratios can be used with differing pre-test probabilities to calculate relevant post- test probabilities and are therefore much more generalizable.
  • the Cochrane collaboration has suggested that positive likelihood ratios of greater than 10 and negative likelihood ratios of less than 0.1 are likely to make a significant impact on health care. As can be seen from the data presented herein, these ratios are met with a risk score of 47 and 43, respectively.
  • the inventors have confirmed the association with the MHC and disease severity in UC and the data shows that there may be more than one 'signal' from this locus. Furthermore, the inventors have also implicated a realistic therapeutic target and known IBD locus, TNFSF15 ⁇ TLIA), suggesting that interference with this pathway is important in severe UC. In addition, the inventors have demonstrated the utility of a model based on GWAS data for predicting the need for surgery in UC. These data demonstrate that the effect of these variants cumulatively they may provide adequate discriminatory power for clinical use. These findings allow a more tailored approach to the management of UC patients and also identify additional targets for early therapeutic intervention in more aggressive UC.
  • mrUC Medically refractory UC
  • mrUC Medically refractory UC
  • the inventors have shown genetic associations with mrUC, which allows for the timely identification of patients at risk for surgery and supports early introduction of more intensive therapy. Genetic loci have been identified as contributing to mrUC using immune-specific Immunochip arrays. These genetic associations also identify novel therapeutic targets for the treatment of severe UC.
  • the inventors performed a stepwise logistic regression and identified 33 SNPs (Analysis I - Logistic regression: mrUC versus non-mrUC; Figure 4) and 8 SNPs (Analysis II - Cox proportional hazards regression) that together were associated with mrUC (logistic regression and Cox proportional hazards; analysis schematic see Figure 5). This analysis resulted in the final risk model of 36 SNPs, which explained 34.7% of risk for colectomy in mrUC ( Figure 6; Table 7).
  • the combination of risk alleles may be useful to identify UC patients at high risk for colectomy.
  • SNPs identified together explain a large proportion of risk: 36 SNPs: 35% risk for colectomy in the mrUC cohort.
  • the inventors calculated a genetic risk score was calculated from the total number of risk alleles (0, 1, or 2) across all 36 risk SNPs (theoretical range: 0-72; observed range: 16-38). Based on the genetic risk scores, the inventors grouped the UC cohort into four risk categories, scores 16-22 (risk- A); scores 23-27 (risk-B); scores 28-32 (risk-C); and scores 33-38 (risk-D).

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Abstract

La présente invention concerne des procédés permettant de prédire le risque de colectomie chez un sujet atteint de CUrm, par une détermination de la présence ou de l'absence d'un ou de plusieurs variants du risque CUrm. D'autres mode de réalisation de l'invention concernent des méthodes de traitement de CUrm chez un sujet et un kit destiné à être utilisé pour le pronostic.
PCT/US2015/029101 2008-12-24 2015-05-04 Procédés de prédiction d'une colite ulcéreuse réfractaire au traitement médical (curm) nécessitant une colectomie Ceased WO2015168699A1 (fr)

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CA2946317A CA2946317A1 (fr) 2014-05-02 2015-05-04 Procedes de prediction d'une colite ulcereuse refractaire au traitement medical (curm) necessitant une colectomie
US15/338,782 US20170044615A1 (en) 2008-12-24 2016-10-31 METHODS OF PREDICTING MEDICALLY REFRACTIVE ULCERATIVE COLITIS (mrUC) REQUIRING COLECTOMY
US16/366,894 US20190218616A1 (en) 2008-12-24 2019-03-27 METHODS OF PREDICTING MEDICALLY REFRACTIVE ULCERATIVE COLITIS (mrUC) REQUIRING COLECTOMY

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US13/140,874 Continuation-In-Part US9580752B2 (en) 2008-12-24 2009-12-24 Methods of predicting medically refractive ulcerative colitis (MR-UC) requiring colectomy
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US10633449B2 (en) 2013-03-27 2020-04-28 Cedars-Sinai Medical Center Treatment and reversal of fibrosis and inflammation by inhibition of the TL1A-DR3 signaling pathway
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US9580752B2 (en) 2008-12-24 2017-02-28 Cedars-Sinai Medical Center Methods of predicting medically refractive ulcerative colitis (MR-UC) requiring colectomy
US10633449B2 (en) 2013-03-27 2020-04-28 Cedars-Sinai Medical Center Treatment and reversal of fibrosis and inflammation by inhibition of the TL1A-DR3 signaling pathway
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