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Human Molecular Genetics Advance Access published online on October 12, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi379
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© The Author 2005. Published by Oxford University Press. All rights reserved The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received March 25, 2005
Revised July 17, 2005
Accepted September 23, 2005

Article

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

Keiko Yamazaki 1, Dermot McGovern 2, Jiannis Ragoussis 3, Marta Paolucci 3, Helen Butler 3, Derek Jewell 2, Lon Cardon 3, Masakazu Takazoe 4, Torao Tanaka 4, Toshiki Ichimori 5, Susumu Saito 6, Akihiro Sekine 6, Aritoshi Iida 6, Atsushi Takahashi 7, Tatsuhiko Tsunoda 7, Mark Lathrop 8, and Yusuke Nakamura 9*

1 Laboratory of Molecular Medicine, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
2 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Gastroenterology Unit, University of Oxford, Oxford, UK
3 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
4 Department of Medicine, Division of Gastroenterology, Social Insurance Chuo General Hospital, Tokyo, Japan
5 Department of Medicine, Division of Gastroenterology, Suzaki Kuroshio Hosipital, Kouchi, Japan
6 Laboratory for Genotyping, SNP Research Center, RIKEN, Yokohama, Japan
7 Laboratory for Medical Informatics, SNP Research Center, RIKEN, Yokohama, Japan
8 Centre National de Genotypage, Evry Cedex, France
9 Laboratory of Molecular Medicine, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan; Laboratory for Genotyping, SNP Research Center, RIKEN, Yokohama, Japan

* To whom correspondence should be addressed.
Yusuke Nakamura, E-mail: yusuke{at}ims.u-tokyo.ac.jp


  Abstract

The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. In order to identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers, and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (p = 1.71 x 10-14 with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.


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