Abstract
Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 × 10−12), a locus on chromosome 13q12 (rs17085007, P = 6.64 × 10−8) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 × 10−8). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis.
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Acknowledgements
We thank all of the patients who participated in this study. We are grateful to F. Hirai, K. Aoyagi, T. Fuchigami, M. Miyazaki, S. Yada, M. Esaki, H. Koga, S. Nakamura, S. Motoya, M. Nomura and T. Sonoda for collecting samples. We thank R. Nakamichi and T. Morizono for help with statistical analysis; participants of the Midosuji and other related Rotary Clubs, Hisayama residents and staff of the Division of Health and Welfare of Hisayama for cooperation in this study; and K. Ashikawa, H. Amitani and other staff of the Laboratory for Genotyping Development, Center for Genomic Medicine, for contributions to this study. This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology.
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Y.N., N.K., M.K. and K.A. designed the study. K.A., T. Matsushita and N.H. performed the genotyping. A.T., T.K., T.T. and N.K. performed the data analyses. J.U., T. Matsumoto, T. Matsui and Y. Kiyohara managed the DNA samples and clinical information of the GWAS. Y. Kakuta, Y. Kinouchi and T.S. performed the genotyping in the first replication study. M.H., Y.A. and Y.S. performed the genotyping in the second replication study. Y.N., M.K., J.U. and K.A. wrote the manuscript. M.I., Y.N. and M.K. supervised the study.
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Asano, K., Matsushita, T., Umeno, J. et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41, 1325–1329 (2009). https://doi.org/10.1038/ng.482
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DOI: https://doi.org/10.1038/ng.482
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