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A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population

Nature Genetics volume 41, pages 1325–1329 (2009)Cite this article

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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Figure 1: Results for association of the extended MHC region (Chr. 6, 24–38 Mb) with ulcerative colitis.
Figure 2: Association mapping and LD structure of the ulcerative colitis–associated region around FCGR2A.
Figure 3: Fine mapping of ulcerative colitis–associated regions across 13q12.13, 7q31.1 and 9p24.1 using screening samples.

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References

  1. Podolsky, D.K. Inflammatory bowel disease. N. Engl. J. Med. 347, 417–429 (2002).

    Article  CAS  Google Scholar 

  2. Loftus, E.V. Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004).

    Article  Google Scholar 

  3. Halme, L. et al. Family and twin studies in inflammatory bowel disease. World J. Gastroenterol. 12, 3668–3672 (2006).

    Article  Google Scholar 

  4. Yamazaki, K. et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum. Mol. Genet. 14, 3499–3506 (2005).

    Article  CAS  Google Scholar 

  5. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  Google Scholar 

  6. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

    Article  CAS  Google Scholar 

  7. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  8. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  9. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    Article  CAS  Google Scholar 

  10. Silverberg, M.S. et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat. Genet. 41, 216–220 (2009).

    Article  CAS  Google Scholar 

  11. Franke, A. et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat. Genet. 40, 713–715 (2008).

    Article  CAS  Google Scholar 

  12. Anderson, C.A. et al. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 136, 523–529 (2009).

    Article  Google Scholar 

  13. Yamazaki, K. et al. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease. J. Hum. Genet. 47, 469–472 (2002).

    Article  CAS  Google Scholar 

  14. Yamazaki, K. et al. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. J. Hum. Genet. 52, 575–583 (2007).

    Article  CAS  Google Scholar 

  15. Yamaguchi-Kabata, Y. et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am. J. Hum. Genet. 83, 445–456 (2008).

    Article  CAS  Google Scholar 

  16. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

  17. Futami, S. et al. HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression. Dig. Dis. Sci. 40, 814–818 (1995).

    Article  CAS  Google Scholar 

  18. Takai, T. Roles of Fc receptors in autoimmunity. Nat. Rev. Immunol. 2, 580–592 (2002).

    Article  CAS  Google Scholar 

  19. Salmon, J.E. et al. FcγRIIA alleles are heritable risk factors for lupus nephritis in African Americans. J. Clin. Invest. 97, 1348–1354 (1996).

    Article  CAS  Google Scholar 

  20. Harley, J.B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Article  CAS  Google Scholar 

  21. Alizadeh, B.Z. et al. Association analysis of functional variants of the FcγRIIa and FcγRIIIa genes with type 1 diabetes, celiac disease and rheumatoid arthritis. Hum. Mol. Genet. 16, 2552–2559 (2007).

    Article  CAS  Google Scholar 

  22. Fanciulli, M. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39, 721–723 (2007).

    Article  CAS  Google Scholar 

  23. Farrell, R.J. & Peppercorn, M.A. Ulcerative colitis. Lancet 359, 331–340 (2002).

    Article  Google Scholar 

  24. Clavel, C. et al. Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 58, 678–688 (2008).

    Article  CAS  Google Scholar 

  25. Lu, J. et al. Structural recognition and functional activation of FcγR by innate pentraxins. Nature 456, 989–992 (2008).

    Article  CAS  Google Scholar 

  26. Hoglund, P. et al. Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat. Genet. 14, 316–319 (1996).

    Article  CAS  Google Scholar 

  27. Moseley, R.H. et al. Downregulated in adenoma gene encodes a chloride transporter defective in congenital chloride diarrhea. Am. J. Physiol. 276, G185–G192 (1999).

    CAS  PubMed  Google Scholar 

  28. Yang, H. et al. Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea. Am. J. Physiol. 275, G1445–G1453 (1998).

    Article  CAS  Google Scholar 

  29. Gill, R.K. et al. Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli. J. Clin. Invest. 117, 428–437 (2007).

    Article  CAS  Google Scholar 

  30. Kiyohara, Y. et al. Ten-year prognosis of stroke and risk factors for death in a Japanese community: the Hisayama study. Stroke 34, 2343–2347 (2003).

    Article  Google Scholar 

  31. Lennard-Jones, J.E. Classification of inflammatory bowel disease. Scand. J. Gastroenterol. Suppl. 170, 2–6 (1989).

    Article  CAS  Google Scholar 

  32. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  Google Scholar 

  33. Hosono, N. et al. Multiplex PCR-based real-time invader assay (mPCR-RETINA): a novel SNP-based method for detecting allelic asymmetries within copy number variation regions. Hum. Mutat. 29, 182–189 (2008).

    Article  CAS  Google Scholar 

Download references

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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Authors and Affiliations

  1. Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama Institute, Yokohama, Japan

    Kouichi Asano, Tomonaga Matsushita, Junji Umeno, Naoya Hosono & Michiaki Kubo

  2. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kouichi Asano, Tomonaga Matsushita, Junji Umeno, Takayuki Matsumoto, Mitsuo Iida & Michiaki Kubo

  3. Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kouichi Asano, Yutaka Kiyohara & Michiaki Kubo

  4. Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Yokohama Institute, Japan

    Atsushi Takahashi & Naoyuki Kamatani

  5. Laboratory for Medical Informatics, Center for Genomic Medicine, RIKEN, Yokohama Institute, Japan

    Takahisa Kawaguchi & Tatsuhiko Tsunoda

  6. Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan

    Toshiyuki Matsui

  7. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yoichi Kakuta, Yoshitaka Kinouchi & Tooru Shimosegawa

  8. First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

    Masayo Hosokawa, Yoshiaki Arimura & Yasuhisa Shinomura

  9. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

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  1. Kouichi Asano
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Contributions

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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Correspondence to Michiaki Kubo.

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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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