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Association Between the PTPN2 Gene and Crohn's Disease: Dissection of Potential Causal Variants

Marcil, Valerie PhD1; Mack, David R. MD2; Kumar, Vijay PhD3; Faure, Christophe MD1,4; Carlson, Christopher S. PhD5; Beaulieu, Patrick PhD1; Israel, David MD6; Krupoves, Alfreda MD, PhD1,7; Costea, Irina MD, PhD8; Lambrette, Philippe MSc1; Grimard, Guy MD1,9; Dong, Jinsong BSc1; Seidman, Ernest G. MD1,10; Amre, Devendra K. MBBS, PhD1,4; Levy, Emile PhD1,11

doi: 10.1097/MIB.0b013e318280b181
Original Clinical Article

Background: Although genome-wide association studies (GWAS) and subsequent meta-analyses have confirmed associations between the PTPN2 (protein tyrosine phosphatase, nonreceptor type 2) gene and Crohn's disease (CD), the potential causal variants remain unidentified. We aimed to dissect potential causal CD-associated PTPN2 variants, assess their functional significance, and relate PTPN2 protein expression with inflammation in CD.

Methods: A 3-stage study was carried out. In stage 1, we genotyped tagging single nucleotide polymorphisms (tag-SNPs) in the PTPN2 gene in a sample of patients with CD (<20 years, n = 556) and controls (n = 602). In stage 2, we resequenced the putative promoter, target exons and introns in the PTPN2 gene, and examined associations with high-frequency variants with CD in the stage 1 cohort. In stage 3 we studied the relationship between PTPN2 protein expression and mucosal inflammation and carried out in silico analyses to study the functional characteristics of the PTPN2 CD-associated SNPs.

Results: In stage 1, we observed associations between 5 intronic SNPs and CD including rs1893217 (P = 2 × 10−4), the SNP that is in perfect linkage disequilibrium with the lead genome-wide association studies SNP rs2542151. Resequencing revealed 2 known promoter polymorphisms. No associations between these promoter SNPs and CD were evident. In silico analyses revealed that the 5 associated intronic SNPs influenced PTPN2 expression and binding to important transcription factors. PTPN2 protein was overexpressed in inflamed intestinal tissues of patients with CD.

Conclusions: Our findings suggest that noncoding variation in the PTPN2 gene may represent the causal variations influencing susceptibility for CD.

Supplemental Digital Content is Available in the Text.Article first published online 20 March 2013

1Research Institute, McGill University, Montreal, Quebec, Canada;

2Division of Gastroenterology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada;

3Research Centre, CHU-Ste-Justine, Montreal, Quebec, Canada;

4Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada;

5Department of Public Health, University of Washington, Seattle, Washington;

6Division of Gastroenterology, Hepatology & Nutrition, British Columbia's Children's Hospital, Vancouver, British Columbia, Canada;

7Department of Preventive and Social Medicine, University of Montreal, Montreal, Quebec, Canada;

8Public Health Agency of Canada, Montreal, Quebec, Canada;

9Division of Orthopaedics, Department of Paediatrics, University of Montreal, Montreal, Quebec, Canada;

10Faculty of Medicine, Division of Gastroenterology, McGill University, Montreal, Quebec, Canada; and

11Department of Nutrition, University of Montreal, Montreal, Quebec, Canada.

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

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 (

Supported by the Canadian Institutes of Health Research (CIHR-IBD NET GRANT, Institute of Infection & Immunity). Dr. D. K. Amre was supported by a research salary award from the Fonds de la Recherché en Santé du Québec (FRSQ), Québec. Dr. I. Costea was supported by a doctoral award from the FRSQ. Dr. A. Krupoves was supported by a scholarship from the Sainte-Justine Hospital Foundation, Montreal and by a scholarship from the PhD Program of the University of Montreal, Montreal.

Received July 24, 2012

Accepted August 14, 2012

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