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Distinct and overlapping genetic loci in crohn's disease and ulcerative colitis: Correlations with pathogenesis

Waterman, Matti MD1; Xu, Wei PhD2; Stempak, Joanne M. MSc1; Milgrom, Raquel MD1; Bernstein, Charles N. MD3; Griffiths, Anne M. MD4,5; Greenberg, Gordon R. MD1,4; Steinhart, Hillary A. MD MSc1,4; Silverberg, Mark S. MD, PhD1,4*

Inflammatory Bowel Diseases:
doi: 10.1002/ibd.21579
Original Basic Science Articles
Abstract

Background:: A common genotypic basis for ulcerative colitis (UC) and Crohn's disease (CD) is implied by overlapping clinical characteristics, epidemiological studies, and association of genes with both UC and CD. We evaluated the overlap between CD and UC genetic loci stratified by pathogenetic pathways and by disease location.

Methods:: The allele frequencies of six UC‐associated and 34 CD‐associated single nucleotide polymorphisms (SNPs) were determined in a Canadian IBD cohort (n = 2374). Differences between CD, UC, colon‐only CD, ileal CD, and controls were analyzed controlling for ethnicity, age of diagnosis, and gender.

Results:: In all, 21 of 34 CD‐associated SNPs had similar allele frequencies in UC (n = 1230) and CD (n = 1144). Three of six UC‐associated SNPs had significantly different frequencies in CD (n = 1144). Most of the divergence in allele frequency among CD and UC was noted in NOD2/autophagy pathway SNPs, while most SNPs with similar frequencies were in IL‐22/23 Th17, adaptive immunity, and barrier pathways. Colon‐only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA‐DRA, and IL‐23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated. In all, 29 of 34 CD SNPs had similar allele frequencies in colonic CD compared with ileal CD (n = 366). All UC SNPs had similar frequencies in UC and colonic CD.

Conclusions:: Our results suggest that CD and UC share common genetic associations related to impaired adaptive immunity and diverge in pathways of foreign antigen processing. Colon‐only CD overlaps extensively with UC and considerably with ileal CD. (Inflamm Bowel Dis 2010)

Author Information

1Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, ON

2Dalla Lana School of Public Health, University of Toronto, ON

3Division of Gastroenterology, University of Manitoba, Winnipeg, MB

4Faculty of Medicine, University of Toronto, Toronto ON

5Division of Gastroenterology, Hospital for Sick Children, Toronto ON, Canada

*Reprints: Mount Sinai Hospital, Division of Gastroenterology, 600 University Ave., Rm. 441, Toronto ON M5G1X5, Canada

Email: msilverberg@mtsinai.on.ca

Received 8 October 2010; Accepted 18 October 2010

Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).

Grant sponsor: Crohn's and Colitis Foundation of Canada (CCFC); Grant sponsor: National Institutes of Health (NIH)/NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases); Grant sponsor: Dr. Silverberg's Gale and Graham Wright Research Chair in Digestive Diseases at Mount Sinai Hospital.

Supported by funding from the Crohn's and Colitis Foundation of Canada (CCFC), National Institutes of Health (NIH)/NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases), and Dr. Silverberg's Gale and Graham Wright Research Chair in Digestive Diseases at Mount Sinai Hospital.

© Crohn's & Colitis Foundation of America, Inc.

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