US20160090629A1 - Variants of tnfsf15 and dcr3 associated with crohn's disease - Google Patents

Variants of tnfsf15 and dcr3 associated with crohn's disease Download PDF

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US20160090629A1
US20160090629A1 US14/890,712 US201414890712A US2016090629A1 US 20160090629 A1 US20160090629 A1 US 20160090629A1 US 201414890712 A US201414890712 A US 201414890712A US 2016090629 A1 US2016090629 A1 US 2016090629A1
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Dermot P. McGovern
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Cedars Sinai Medical Center
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    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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    • C12Q2600/172—Haplotypes

Definitions

  • the claimed invention relates to prognosis, diagnosis and treatment of inflammatory bowel disease and related conditions, including methods and compositions for medical therapies.
  • IBD Inflammatory bowel disease
  • CD Crohn's disease
  • TL1A may drive intestinal inflammation through enhancing Th1, Th2 and Th17 effector function
  • TL1A appears to also drive fibrogenesis through increased number of fibroblasts and activated fibroblasts and constitutive TL1A expression in mice has been found to confer worsened murine ileo-cecal inflammation, and intestinal fibrostenosis.
  • TNFSF15 TNF superfamily member
  • DcR3 a known IBD susceptibility gene
  • FIG. 1 depicts, in accordance with embodiments herein, principal component analysis (PC1/PC2).
  • FIG. 2 depicts, in accordance with embodiments herein, pACTs of TNFSF15 region in NJ (Non-Jewish) and AJ (Ashkenazi Jewish) CD.
  • FIG. 3 depicts, in accordance with embodiments herein, pACTs of DcR3 (TNFRSF6B) region in NJ and AJ CD.
  • FIG. 4 depicts, in accordance with embodiments herein, linkage disequilibrium maps (r 2 ) of the associated TNFSF15 SNPs in NJ and SK.
  • Described herein is an assay for quantifying risk in a subject to Crohn's disease and/or fibrosist, including obtaining a sample from a subject, subjecting the sample to a genotyping assay adapted to determine the presence or absence of one or more variants at the TNFSF15 and/or DcR3 genetic loci, and quantifying risk in a subject to Crohn's disease and/or fibrosis based on the presence of one or more variants at the TNFSF15 and/or DcR3genetic loci.
  • the variants include one or more variants selected from the group including: SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO.
  • the variants are SEQ ID NO. 3 and/or SEQ ID NO.13. In other embodiments, the variant is SEQ ID NO. 22.
  • the subject is non-Jewish Caucasian, Ashkenazi, South Korean and/or Puerto Rican.
  • the subject is South Korean and the variant are SEQ ID NO. 3, SEQ ID NO.13 and/or SEQ ID NO. 22.
  • the variant is a risk variant.
  • the variant is a protective variant.
  • the protective variant quantifies a reduced risk in the subject for structuring, CD, small bowel involvement and/or need for surgical intervention.
  • variants consist of one or more variants selected from the group including: SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO.
  • variants are SEQ ID NO. 3 and/or SEQ ID NO.13.
  • variant is SEQ ID NO. 22.
  • subject is non-Jewish Caucasian, Ashkenazi, South Korean and/or Puerto Rican.
  • subject is South Korean and the variant are SEQ ID NO. 3, SEQ ID NO.13 and/or SEQ ID NO. 22.
  • the variants consist of one or more variants selected from the group including: 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, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO.
  • 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, SEQ ID NO. 25, and SEQ ID NO. 26.
  • TL1A is the product of the TNFSF15 gene that is expressed by both lymphoid and myeloid derived cells. Variants in the TNFSF15 gene have been found to be associated with IBD.
  • TNFSF15 The protein product of TNFSF15, TL1A, is elevated in the intestinal mucosa of IBD patients.
  • Certain TNFSF15 haplotypes are associated with susceptibility in non-Jewish Caucasian CD and UC.
  • TNFSF15 haplotype B is not only associated with risk, but also with severity in Jewish CD patients.
  • monocytes from Jewish patients carrying the risk haplotype B express higher levels of TL1A in response to FcyR stimulation.
  • TL1A signals via death domain receptor 3 (DR3) and several studies implicate the TL1A/DR3 signaling pathway in mucosal inflammation.
  • DR3 death domain receptor 3
  • TL1A/DR3 signaling pathway in mucosal inflammation.
  • Neutralizing TL1A-antibody ameliorates inflammation in DSS and G ⁇ i2-/- T cell transfer chronic colitis models.
  • Constitutive TL1A expression in mice leads to mild spontaneous ileitis and increased collagen deposition.
  • TL1A modulates the adaptive immune response in the T-helper (Th)-1 effector arm, as shown by TL1A enhanced interferon (IFN)- ⁇ production from peripheral and mucosal T-cells.
  • TL1A is a TNF superfamily member.
  • TNFSF15 haplotype B has increased TL1A expression with a higher risk of small bowel surgery, and constitutive T11a expression in mice confers worsened murine ileo-cecal inflammation and intestinal fibrostenosis. While it is known TL1A can enhance Th1, Th2, and Th17 effector cell function, it is poorly understood which TL1A activated T-helper effector pathway induces intestinal inflammation and fibrosis. Thus, a critical scientific question is understanding the effect of T-helper pathway on TL1A induced colitis and effect of T-helper pathway on TL1A induced gut fibrosis.
  • the inventors performed trans-ethnic fine mapping across TNFSF15 and DcR3 in Caucasian, Puerto Rican, and Korean CD.
  • the inventors identified associations with Non Jewish Caucasian (NJ) Crohn's disease (CD) and rare TNFSF15 variants. This association is independent of previously reported common variants. Also, these variants are much more common in the South Korean (SK) population, and also associated with SK CD.
  • DcR3 is significantly associated with NJ CD, a finding replicated in SK and variation at this locus modifies stricturing phenotype.
  • Described herein is an assay for quantifying risk in a subject to Crohn's disease and/or fibrosist, including obtaining a sample from a subject, subjecting the sample to a genotyping assay adapted to determine the presence or absence of one or more variants at the TNFSF15 and/or DcR3 genetic loci, and quantifying risk in a subject to Crohn's disease and/or fibrosis based on the presence of one or more variants at the TNFSF15 and/or DcR3genetic loci.
  • the variants include one or more variants selected from the group including: SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO.
  • the variants are SEQ ID NO. 3 and/or SEQ ID NO.13. In other embodiments, the variant is SEQ ID NO. 22.
  • the subject is non-Jewish Caucasian, Ashkenazi, South Korean and/or Puerto Rican.
  • the subject is South Korean and the variant are SEQ ID NO. 3, SEQ ID NO.13 and/or SEQ ID NO. 22.
  • the variant is a risk variant.
  • the variant is a protective variant.
  • the protective variant quantifies a reduced risk in the subject for structuring, CD, small bowel involvement and/or need for surgical intervention.
  • variants consist of one or more variants selected from the group including: SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO.
  • variants are SEQ ID NO. 3 and/or SEQ ID NO.13.
  • variant is SEQ ID NO. 22.
  • subject is non-Jewish Caucasian, Ashkenazi, South Korean and/or Puerto Rican.
  • subject is South Korean and the variant are SEQ ID NO. 3, SEQ ID NO.13 and/or SEQ ID NO. 22.
  • the variants consist of one or more variants selected from the group including: 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, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO.
  • 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, SEQ ID NO. 25, and SEQ ID NO. 26.
  • the present invention provides a method of diagnosing susceptibility to Crohn's disease in a subject by obtaining a sample from the subject, assaying the sample to determine the presence or absence of one or more risk variants in the subject, and diagnosing susceptibility to Crohn's disease based on the presence of one or more risk variants.
  • the one or more risk variants are at the TNFSF15 and/or DcR3 genetic loci.
  • the one or more risk variants are described in Tables 2 and 3 herein.
  • the subject is Caucasian, Puerto Spainn, or South Korean.
  • the subject is Non-Caucasian.
  • the present invention provides a method of diagnosing a Crohn's disease subtype in a subject by obtaining a sample from the subject, assaying the sample to determine the presence or absence of one or more risk variants in the subject, and diagnosing the Crohn's disease subtype based on the presence of one or more risk variants.
  • the one or more risk variants are at the TNFSF15 and/or DcR3 genetic loci.
  • the one or more risk variants are described in Tables 2 and 3 herein.
  • the subject is Caucasian, Puerto Spainn, or South Korean.
  • the subject is Non-Caucasian.
  • the present invention provides a method of treating Crohn's disease in a subject by determining the presence of one or more one or more risk variants in the subject, and treating the subject.
  • the one or more risk variants are at the TNFSF15 and/or DcR3 genetic loci.
  • the one or more risk variants are described in Tables 2 and 3 herein.
  • the subject is Caucasian, Puerto Spainn, or South Korean.
  • the subject is Non-Caucasian.
  • the present invention provides a method of diagnosing susceptibility to fibrosis in a subject by obtaining a sample from the subject, assaying the sample to determine the presence or absence of one or more risk variants in the subject, and diagnosing susceptibility to fibrosis based on the presence of one or more risk variants.
  • the one or more risk variants are at the TNFSF15 and/or DcR3 genetic loci.
  • the one or more risk variants are described in Tables 2 and 3 herein.
  • the subject is Caucasian, Puerto Spainn, or South Korean.
  • the subject is Non-Caucasian.
  • the present invention provides a method of diagnosing a fibrosis subtype in a subject by obtaining a sample from the subject, assaying the sample to determine the presence or absence of one or more risk variants in the subject, and diagnosing the fibrosis subtype based on the presence of one or more risk variants.
  • the one or more risk variants are at the TNFSF15 and/or DcR3 genetic loci.
  • the one or more risk variants are described in Tables 2 and 3 herein.
  • the subject is Caucasian, Puerto Spainn, or South Korean.
  • the subject is Non-Caucasian.
  • the present invention provides a method of treating fibrosis in a subject by determining the presence of one or more one or more risk variants in the subject, and treating the subject.
  • the one or more risk variants are at the TNFSF15 and/or DcR3 genetic loci.
  • the one or more risk variants are described in Tables 2 and 3 herein.
  • the subject is Caucasian, Puerto Spainn, or South Korean.
  • the subject is Non-Caucasian.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • the inventors performed trans-ethnic fine mapping across TNFSF15 and DcR3 in Caucasian, Puerto Rican (PR) and South Korean (SK) CD. Immunochip genotyping as performed on the following populations presented in Table 1.
  • TNFSF15-130 4.89E ⁇ 05 8.70E ⁇ 01 1.54E ⁇ 01 6.92E ⁇ 17 6.62 1.05 1.31 2.10 TNFSF15-150 4.12E ⁇ 05 7.23E ⁇ 01 3.10E ⁇ 02 5.28E ⁇ 17 8.95 1.13 1.75 2.12 TNFSF15-160 3.02E ⁇ 06 5.81E ⁇ 01 3.19E ⁇ 02 8.66E ⁇ 17 6.97 0.84 1.67 2.10 TNFSF15-271 4.48E ⁇ 05 7.99E ⁇ 01 1.25E ⁇ 02 3.15E ⁇ 10 6.70 1.09 2.02 1.76 Common Variants of TNFSF15 TNFSF15-90 5.31E ⁇ 05 2.92E ⁇ 01 3.70E ⁇ 01 5.70E ⁇ 16 1.30 0.88 1.15 2.26 TNFSF15-106 7.98E ⁇ 05 1.34E
  • TNFSF15-DcR3 SNPs SNP Gene NJ CD SK CD TNFSF15-160 TNFSF15 1.4% 41.4% TNFSF15-164 TNFSF15 17.0% 70.8% DcR3-9 DcR3 20.5% 9.0% TNFSF15-DCR3 3 SNPs — 32.3% 76.4%
  • the ‘rare’ and ‘common’ variants can each be tagged by a single SNP (SNP160 & SNP164 respectively) in both NJ and SK.
  • SNP160 & SNP164 SNP160 & SNP164 respectively
  • the ‘rare’ variants were associated with CD in PR (at higher allele frequency). No association was seen in PR with the common variants. (Table 4). No significant SNP associations were observed in AJ CD. ( FIG. 2 , Table 4). After correcting for multiple comparisons there were no significant associations with rare or common CD-associated SNPs with clinical subphenotypes in NJ CD.
  • the inventors identified associations with NJ CD and rare TNFSF15 variants. This association is independent of previously reported common variants. These variants are much more common in the SK population, and also associated with SK CD. DcR3 is significantly associated with NJ CD, a finding replicated in SK and variation at this locus modifies stricturing phenotype.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

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US10316083B2 (en) 2013-07-19 2019-06-11 Cedars-Sinai Medical Center Signature of TL1A (TNFSF15) signaling pathway
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
US11186872B2 (en) 2016-03-17 2021-11-30 Cedars-Sinai Medical Center Methods of diagnosing inflammatory bowel disease through RNASET2
US11236393B2 (en) 2008-11-26 2022-02-01 Cedars-Sinai Medical Center Methods of determining responsiveness to anti-TNFα therapy in inflammatory bowel disease

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EP3846851A4 (en) * 2018-09-07 2022-09-21 The Children's Hospital Of Philadelphia COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING DISORDERS OF THE LYMPHATIC SYSTEM
CA3140029A1 (en) 2019-05-14 2020-11-19 Prometheus Biosciences, Inc. Tl1a patient selection methods, systems, and devices
EP4056232A4 (en) * 2019-09-13 2023-09-13 Kyowa Kirin Co., Ltd. DCR3 VARIANT

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