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Mapping of a disease susceptibility locus in chromosome 6p in Japanese patients with ulcerative colitis

Genes & Immunity volume 5, pages 477–483 (2004)Cite this article

Abstract

Ulcerative colitis (UC) is a multifactorial disorder with both genetic and environmental factors. HLA-B*52 and DRB1*1502 are reported to be strongly associated with UC in Japan. However, the actual susceptible gene has not been identified yet. In this study, to map precisely the susceptible locus for UC, we performed association mapping in the chromosome 6p using 24 microsatellite markers distributed over 16 Mb. A total of 183 patients with UC and 186 healthy controls (HC) were included in this study. In all, 15 markers around the human leukocyte antigen (HLA) region showed statistical significance in the genotypic differentiation test concerned with the allelic distribution between the UC and HC. Especially, the markers between the centromeric region of HLA class I and the telomeric region of class III showed remarkably low P-values and the allele239 of C2-4-4 in class I marker showed the strongest association (Pc=2.9 × 10−9: OR=3.74, 95% CI=2.50–5.60). Furthermore, we found strong linkage disequilibrium (LD) between the allele239 of C2-4-4 and HLA-B*52 in haplotype analysis. These results provide evidence that, in Japanese, important determinants of disease susceptibility to UC may exist in HLA, especially between the centromeric region of class I and the telomeric region of class III, under the strong LD with HLA-B*52.

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References

  1. Maratka Z, Sera J . Familiar occurrence of ulcerative colitis. Gastroenterologia 1965; 103: 321–325.

    Article  CAS  Google Scholar 

  2. Mayberry JF . Recent epidemiology of ulcerative colitis and Crohn's disease. Int J Colorectal Dis 1989; 4: 59–66.

    Article  CAS  Google Scholar 

  3. Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen IA, Binder V . Familial occurrence of inflammatory bowel disease. N Engl J Med 1991; 324: 84–88.

    Article  CAS  Google Scholar 

  4. Satsangi J, Grootscholten C, Holt H, Jewell DP . Clinical patterns of familial inflammatory bowel disease. Gut 1996; 38: 738–741.

    Article  CAS  Google Scholar 

  5. Cipolla C, Magliocco A, Oliva L, Cottone M . Familial aggregation of inflammatory bowel disease in a Mediterranean area. Eur J Epidemiol 1996; 12: 205–210.

    Article  CAS  Google Scholar 

  6. Russel MG, Pastoor CJ, Janssen KM et al. Familial aggregation of inflammatory bowel disease: a population-based study in South Limburg, The Netherlands. The South Limburg IBD Study Group. Scand J Gastroenterol Suppl 1997; 223: 88–91.

    CAS  PubMed  Google Scholar 

  7. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B . Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988; 29: 990–996.

    Article  CAS  Google Scholar 

  8. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ . Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 1996; 312: 95–96.

    Article  CAS  Google Scholar 

  9. Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO . Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000; 35: 1075–1081.

    Article  CAS  Google Scholar 

  10. Roth MP, Petersen GM, McElree C, Feldman E, Rotter JI . Geographic origins of Jewish patients with inflammatory bowel disease. Gastroenterology 1989; 97: 900–904.

    Article  CAS  Google Scholar 

  11. Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP . Review article: the genetics of inflammatory bowel disease. Aliment Pharmacol Ther 2001; 15: 731–748.

    Article  CAS  Google Scholar 

  12. Hampe J, Schreiber S, Shaw SH et al. A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 1999; 64: 808–816.

    Article  CAS  Google Scholar 

  13. Hampe J, Shaw SH, Saiz R et al. Linkage of inflammatory bowel disease to human chromosome 6p. Am J Hum Genet 1999; 65: 1647–1655.

    Article  CAS  Google Scholar 

  14. Rioux JD, Silverberg MS, Daly MJ et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000; 66: 1863–1870.

    Article  CAS  Google Scholar 

  15. Dechairo B, Dimon C, van Heel D et al. Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3). Eur J Hum Genet 2001; 9: 627–633.

    Article  CAS  Google Scholar 

  16. Satsangi J, Parkes M, Louis E et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 1996; 14: 199–202.

    Article  CAS  Google Scholar 

  17. Curran ME, Lau KF, Hampe J et al. Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16. Gastroenterology 1998; 115: 1066–1071.

    Article  CAS  Google Scholar 

  18. Cho JH, Nicolae DL, Gold LH et al. Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci USA 1998; 95: 7502–7507.

    Article  CAS  Google Scholar 

  19. Duerr RH, Barmada MM, Zhang L et al. Linkage and association between inflammatory bowel disease and a locus on chromosome 12. Am J Hum Genet 1998; 63: 95–100.

    Article  CAS  Google Scholar 

  20. Mirza MM, Lee J, Teare D et al. Evidence of linkage of the inflammatory bowel disease susceptibility locus on chromosome 16 (IBD1) to ulcerative colitis. J Med Genet 1998; 35: 218–221.

    Article  CAS  Google Scholar 

  21. Cho JH, Nicolae DL, Ramos R et al. Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease. Hum Mol Genet 2000; 9: 1425–1432.

    Article  CAS  Google Scholar 

  22. Cho J . Linkage of inflammatory bowel disease to human chromosome 6p. Inflamm Bowel Dis 2000; 6: 259–261.

    Article  CAS  Google Scholar 

  23. Asakura H, Tsuchiya M, Aiso S et al. Association of the human lymphocyte-DR2 antigen with Japanese ulcerative colitis. Gastroenterology 1982; 82: 413–418.

    CAS  PubMed  Google Scholar 

  24. Delpre G, Kadish U, Gazit E, Joshua H, Zamir R . HLA antigens in ulcerative colitis and Crohn's disease in Israel. Gastroenterology 1980; 78: 1452–1457.

    CAS  PubMed  Google Scholar 

  25. Leidenius MH, Koskimies SA, Kellokumpu IH, Hockerstedt KA . HLA antigens in ulcerative colitis and primary sclerosing cholangitis. Apmis 1995; 103: 519–524.

    Article  CAS  Google Scholar 

  26. Habeeb MA, Rajalingam R, Dhar A, Kumar A, Sharma MP, Mehra NK . HLA association and occurrence of autoantibodies in Asian-Indian patients with ulcerative colitis. Am J Gastroenterol 1997; 92: 772–776.

    CAS  PubMed  Google Scholar 

  27. Futami S, Aoyama N, Honsako Y et al. HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression. Dig Dis Sci 1995; 40: 814–818.

    Article  CAS  Google Scholar 

  28. Yoshitake S, Kimura A, Okada M, Yao T, Sasazuki T . HLA class II alleles in Japanese patients with inflammatory bowel disease. Tissue Antigens 1999; 53: 350–358.

    Article  CAS  Google Scholar 

  29. Sugimura K, Asakura H, Mizuki N et al. Analysis of genes within the HLA region affecting susceptibility to ulcerative colitis. Hum Immunol 1993; 36: 112–118.

    Article  CAS  Google Scholar 

  30. Toyoda H, Wang SJ, Yang HY et al. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology 1993; 104: 741–748.

    Article  CAS  Google Scholar 

  31. Tamiya G, Shiina T, Oka A et al. New polymorphic microsatellite markers in the human MHC class I region. Tissue Antigens 1999; 54: 221–228.

    Article  CAS  Google Scholar 

  32. Tamiya G, Ota M, Katsuyama Y et al. Twenty-six new polymorphic microsatellite markers around the HLA-B, -C and -E loci in the human MHC class I region. Tissue Antigens 1998; 51: 337–346.

    Article  CAS  Google Scholar 

  33. Matsuzaka Y, Makino S, Nakajima K et al. New polymorphic microsatellite markers in the human MHC class II region. Tissue Antigens 2000; 56: 492–500.

    Article  CAS  Google Scholar 

  34. Matsuzaka Y, Makino S, Nakajima K et al. New polymorphic microsatellite markers in the human MHC class III region. Tissue Antigens 2001; 57: 397–404.

    Article  CAS  Google Scholar 

  35. Ota M, Mizuki N, Katsuyama Y et al. The critical region for Behçet disease in the human major histocompatibility complex is reduced to a 46-kb segment centromeric of HLA-B, by association analysis using refined microsatellite mapping. Am J Hum Genet 1999; 64: 1406–1410.

    Article  CAS  Google Scholar 

  36. Oka A, Tamiya G, Tomizawa M et al. Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene. Hum Mol Genet 1999; 8: 2165–2170.

    Article  CAS  Google Scholar 

  37. Herr M, Dudbridge F, Zavattari P et al. Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21. Hum Mol Genet 2000; 9: 1291–1301.

    Article  CAS  Google Scholar 

  38. Ota M, Katsuyama Y, Kimura A et al. A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region. Genomics 2001; 71: 263–270.

    Article  CAS  Google Scholar 

  39. Oka A, Hayashi H, Tomizawa M et al. Localization of a non-melanoma skin cancer susceptibility region within the major histocompatibility complex by association analysis using microsatellite markers. Tissue Antigens 2003; 61: 203–210.

    Article  CAS  Google Scholar 

  40. Truelove SC, Jewell DP . Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974; 1: 1067–1070.

    Article  CAS  Google Scholar 

  41. Kruglyak L . Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999; 22: 139–144.

    Article  CAS  Google Scholar 

  42. Tokunaga K, Ishikawa Y, Ogawa A et al. Sequence based association analysis of HLA class I and II alleles in Japanese supports conservation of common haplotypes. Immunogenetics 1997; 46: 199–205.

    Article  CAS  Google Scholar 

  43. Guo SW, Thompson EA . Performing the exact test of Hardy–Weinberg proportion for multiple alleles. Biometrics 1992; 48: 361–372.

    Article  CAS  Google Scholar 

  44. Raymond M, Rousset F . An exact test for population differentiation. Evolution 1995; 49: 1280–1283.

    Article  Google Scholar 

  45. Raymond M, Rousset F . Genepop (version 1*2): population genetics software for exact tests and ecumenicism. J Hered 1997; 86: 248–249.

    Article  Google Scholar 

  46. Terwilliger J, Oh J . Handbook of Human Genetic Linkage. Johns Hopkins University Press: Baltimore, 1994.

    Google Scholar 

  47. Xie X . Testing linkage disequilibrium between a disease gene and marker loci. Am J Hum Genet 1993; 53: 1107.

    Google Scholar 

  48. Kinouchi Y, Matsumoto K, Negoro K et al. Hla-B genotype in Japanese patients with Crohn's disease. Dis Colon Rectum 2003; 46: S10–S14.

    PubMed  Google Scholar 

Download references

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Authors and Affiliations

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

    E Nomura, Y Kinouchi, K Negoro, Y Kojima, S Oomori, M Sugimura, M Hiroki, S Takagi, H Aihara, S Takahashi & T Shimosegawa

  2. Iwaki Kyoritsu General Hospital, Iwaki, Japan

    N Hiwatashi

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  1. E Nomura
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  2. Y Kinouchi
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  3. K Negoro
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Correspondence to E Nomura.

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Nomura, E., Kinouchi, Y., Negoro, K. et al. Mapping of a disease susceptibility locus in chromosome 6p in Japanese patients with ulcerative colitis. Genes Immun 5, 477–483 (2004). https://doi.org/10.1038/sj.gene.6364114

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  • DOI: https://doi.org/10.1038/sj.gene.6364114

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