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Nature Genetics  36, 471 - 475 (2004)
Published online: 11 April 2004; | doi:10.1038/ng1339

Functional variants of OCTN cation transporter genes are associated with Crohn disease

Vanya D Peltekova1, 2, Richard F Wintle3, Laurence A Rubin1, 3, 4, Christopher I Amos5, Qiqing Huang5, Xiangjun Gu5, Bill Newman1, 2, Mark Van Oene3, David Cescon1, 2, Gordon Greenberg1, Anne M Griffiths6, Peter H St George-Hyslop1, 3, 7 & Katherine A Siminovitch1, 2, 3

1  Department of Medicine, University of Toronto, University of Toronto, Toronto, Ontario, Canada, M5S 1A1.

2  Departments of Immunology and of Medical Genetics and Microbiology, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, and Toronto General Research Institutes, Toronto, Ontario, Canada.

3  Ellipsis Biotherapeutics Corporation, 700 Bay Street, Suite 2101, Toronto, Ontario M5G 1Z6, Canada.

4  Division of Rheumatology, St. Michael's Hospital, 30 Bond St., Toronto, Ontario M5B 1W8, Canada.

5  Department of Epidemiology, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

6  Department of Pediatrics, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.

7  Centre for Research in Neurodegenerative Diseases, Tanz Neuroscience Building, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada, and the University Health Network, Toronto, Ontario, Canada.

Correspondence should be addressed to Katherine A Siminovitch
Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of approx250 kb at 5q31 (IBD5)1, 2 was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms3 among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a Gright arrowC transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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