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Genome-wide Association Study Signal at the 12q12 Locus for Crohns Disease May Represent Associations with the MUC19 Gene

Kumar, Vijay PhD*; Mack, David R. MD; Marcil, Valerie PhD; Israel, David MD§; Krupoves, Alfreda PhD*,‖; Costea, Irina PhD; Lambrette, Philippe MSc*; Grimard, Guy MD*,**; Dong, Jinsong BSc*; Seidman, Ernest G. MD††; Amre, Devendra K. MBBS, PhD*; Levy, Emile PhD*,‡‡

doi: 10.1097/MIB.0b013e318281f454
Original Basic Science Article

Background: Genome-wide association studies (GWAS) in Crohn’s disease (CD) have identified associations with single-nucleotide polymorphism (SNP) rs11175593 at chromosome 12q12. The MUC19 and LRRK2 genes reside close to the GWAS signal, but it is as yet unclear which of the 2 genes represent the CD susceptibility genes.

Methods: We studied associations between nonsynonymous coding variants in the MUC19 (5) and LRRK2 (3) genes in a case–control sample comprising CD cases aged <18 years at diagnosis. The GWAS lead SNP rs11175593 was also investigated. Allelic, genotype, and haplotype associations were examined assuming different models of inheritance.

Results: A total of 530 cases and 600 controls were studied. The mean (±SD) age at diagnosis was 12.4 (±3.3). Most cases were male (57.4%). Most patients had ileocolonic disease location (48.8%) and inflammatory behavior at diagnosis (87.0%). Three MUC19 SNPs were nominally significantly associated with CD (rs11564245, Asp→His: P = 0.02; rs4768261, Ser→Phe: P = 0.0008; and rs2933353, Glu→Ala: P = 0.01). Associations with rs4768261 were maintained after corrections for multiple comparisons (permuted, P = 0.007). None of the LRRK2 SNPs were associated with CD. Haplotype analysis supported the single SNP associations noted with the MUC19 gene.

Conclusions: GWAS signal at chromosome 12q12 for CD may represent associations with the MUC19 gene.

Article first published online 9 April 2013

*Division of Gastroenterology, Hepatology & Nutrition, Research Centre, CHU-Ste-Justine, Montreal, Canada;

Division of Gastroenterology, Children’s Hospital of Eastern Ontario, Ottawa, Canada;

Department of Gastroenterology, Research Institute, McGill University, Montreal, Quebec, Canada;

§Division of Gastroenterology, Hepatology & Nutrition, British Columbia’s Children’s Hospital, Vancouver, Canada;

Department of Preventive and Social Medicine, University of Montreal, Montreal, Canada;

Center for Communicable Diseases and Infection Control, Public Health Agency of Canada, Montreal, Canada;

**Division of Orthopaedics, Department of Paediatrics, University of Montreal, Montreal, Canada;

††Division of Gastroenterology, Faculty of Medicine, the Research Institute of the McGill University Health Center, McGill University, Montreal, Canada; and

‡‡Department of Nutrition, University of Montreal, Montreal, Canada.

Reprints: Devendra K. Amre, MBBS, PhD, Research Center, CHU-Ste-Justine, Bureau 3734, Ste-Justine Hospital, 3175 Cote-Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5 (e-mail: devendra.amre@umontreal.ca).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Supported by the Canadian Institutes of Health Research (CIHR-IBD NET GRANT, Institute of Infection & Immunity).

D. K. Amre was supported by a research salary award from the Fonds de la Recherché en Santé du Québec (FRSQ), Quebec, Canada. I. Costea was supported by a doctoral award from the FRSQ. A. Krupoves was supported by a scholarship from the Sainte-Justine Hospital Foundation, Montreal, Canada, and by a scholarship from the PhD Program of the University of Montreal, Montreal, Canada.

Received October 16, 2012

Accepted November 13, 2012

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