Investigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

doi:10.1053/j.gastro.2008.10.032

Gastroenterology

Volume 136, Issue 2, February 2009, Pages 523-529.e3

https://doi.org/10.1053/j.gastro.2008.10.032 Get rights and content

Background & Aims

Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD.

Methods

We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls.

Results

Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 × 10⁻⁸; odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD.

Conclusions

Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Section snippets

Subjects/Genotyping

A total of 3026 UC and 1727 CD patients were recruited in participating centers across the United Kingdom. Diagnosis of UC and CD was based on standard clinical, endoscopic, radiologic, and histologic criteria. Patient demographics, family history, smoking history, and subphenotype data were ascertained by combination of questionnaire and case note review. Details of the cases analyzed after quality control are presented in Table 1. Ethics committee approval was granted in each of the four lead

UC Experiment

Of the 45 SNPs included in the study, 13 showed significant association with UC (see supplementary Table 2 online at www.gastrojournal.org), and these comprise 9 independent loci (Table 2). The candidate region showing the strongest association was 1q32. Both SNPs genotyped within this locus showed robust evidence of association (P_rs2297909 = 4.13 × 10⁻⁸, P_rs11584383 = 5.71 × 10⁻⁷). A further 3 loci are novel associations with UC (JAK2, LYRM4, and CDKAL1). Both SNPs genotyped within the JAK2

Discussion

Through follow-up of discoveries from the recent CD meta-analysis, this study identifies 4 new susceptibility loci for UC. In addition, we provide replicated association and thereby confirmation of 3 recently reported UC loci. These results therefore add significantly to the body of evidence for shared pathways between the 2 diseases, an observation of considerable importance both in understanding diseases pathogenesis and in discovering new therapeutic targets.

Choice of appropriate statistical

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To date, a number of studies have been made to explore the relationship between the IL12B (G/A) rs10045431, (T/C) rs6887695 polymorphisms and IBD [9,13–25], and their results were inconsistent. Besides, it was worth noting that almost all studies involved in Caucasian[9,13–24] and only one study involved other races[25]. To eliminate influence of racial differences on result of meta-analysis, we clarify the association between IL12B polymorphisms and IBD risk in Caucasian population.
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: C.A.A. and D.C.O.M. contributed equally to this work.

: The authors disclose the following: Supported by the NIHR Cambridge Biomedical Research Centre, by the Wellcome Trust (to C.A.A.), and by the Medical Research Council (to D.C.O.M.).

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Basic—Alimentary TractInvestigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

Background & Aims

Methods

Results

Conclusions

Section snippets

Subjects/Genotyping

UC Experiment

Discussion

Gastroenterology

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Clin Immunol Immunopathol

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

Nature

A frame shift mutation in NOD2 associated with susceptibility to Crohn's disease

Nature

Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease

Hum Mol Genet

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene

Science

Genome-wide association study identifies new susceptibility loci for Crohn's disease and implicates autophagy in disease pathogenesis

Nat Genet

A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn's disease in ATG16L1

Nat Genet

Novel Crohn's disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4

PLoS Genet

Systematic association mapping identifies NELL1 as a novel IBD disease gene

PLoS ONE

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Nature

Basic—Alimentary Tract
Investigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship