Skip to main content
NCBI home page
Gut logoLink to Gut
. 1999 Sep;45(3):395–401. doi: 10.1136/gut.45.3.395

HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis

P Stokkers 1, P Reitsma 1, G Tytgat 1, S J H van Deventer 1
PMCID: PMC1727649  PMID: 10446108

Abstract

BACKGROUND—Susceptibility to inflammatory bowel disease (IBD) is partially genetically determined and the HLA class II genes are candidates for a role in genetic susceptibility to IBD, because their products play a central role in the immune response. Multiple studies have reported associations between HLA-DR or -DQ phenotypes and either ulcerative colitis or Crohn's disease, but much of the data are still controversial.
AIMS—To estimate overall associations between HLA class II phenotypes and IBD, and to establish the relative risk conferred by HLA-DR and -DQ phenotypes by meta-analysis.
METHODS—Medline was searched for publications reporting on the relation between IBD and HLA class II phenotypes. Raw data were extracted by recalculating the number of phenotypes or the number of alleles of the main antigens. Odds ratios and confidence intervals were calculated according to the Mantel-Haenszel method.
RESULTS—DR2, DR9, and DRB1*0103 were positively associated with ulcerative colitis, and a negative association was found for DR4 and ulcerative colitis. For Crohn's disease a positive association was found with DR7, DRB3*0301, and DQ4 and a negative association with DR2 and DR3.
CONCLUSIONS—Both ulcerative colitis and Crohn's disease are associated with specific HLA class II phenotypes. Further analysis of these phenotypes and subgroup analysis may elucidate how these alleles contribute to susceptibility to IBD.


Keywords: ulcerative colitis; Crohn's disease; HLA-DR; HLA-DQ

Full Text

The Full Text of this article is available as a PDF (116.7 KB).

Figure 1  .

Figure 1  

Open in a new tab

HLA-DR gene nomenclature. The HLA-DR genes are located in the major histocompatibility region on chromosome 6. The DRA gene, encoding the α chain of the molecule is not polymorphic. The DRB 1, 3, 4, and 5 genes are polymorphic. The serological specificities of the DRB1, DRB3, DRB4, and DRB5 polymorphisms and the corresponding genotypes are shown.

Figure 2  .

Figure 2  

Open in a new tab

Associations between HLA-DR/DQ phenotypes and Crohn's disease. The odds ratio is on the x axis. The odds ratios of the individual studies are indicated by the squares, the size indicates the weight of the studies in the meta-analysis, and the lines reflect the confidence intervals. The numbers refer to the study numbers listed in table 1. The diamond depicts the overall odds ratio and confidence interval. (A) HLA-DR2; (B) HLA-DR3; (C) HLA-DR7; (D) HLA-DQ4; (E) HLA-DRB3*0301.

Figure 3  .

Figure 3  

Open in a new tab

HLA-DR/DQ phenotypes and ulcerative colitis. The odds ratio is on the x axis. The odds ratios of the individual studies are indicated by the squares, the size indicates the weight of the studies in the meta-analysis, and the lines reflect the confidence intervals. The numbers refer to the study numbers listed in table 1. The diamond depicts the overall odds ratio and confidence interval. (A) HLA-DR2; (B) HLA-DR4; (C) HLA-DR9; (D) HLA-DRB1*1501; (E) HLA-DRB1*1502; (F) HLA-DRB1*0103.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asakura H., Tsuchiya M., Aiso S., Watanabe M., Kobayashi K., Hibi T., Ando K., Takata H., Sekiguchi S. Association of the human lymphocyte-DR2 antigen with Japanese ulcerative colitis. Gastroenterology. 1982 Mar;82(3):413–418. [PubMed] [Google Scholar]
  2. Bouma G., Oudkerk Pool M., Crusius J. B., Schreuder G. M., Hellemans H. P., Meijer B. U., Kostense P. J., Giphart M. J., Meuwissen S. G., Peña A. S. Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD). Clin Exp Immunol. 1997 Jul;109(1):175–179. doi: 10.1046/j.1365-2249.1997.4121510.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bouma G., Poen A. C., García-González M. A., Schreuder G. M., Felt-Bersma R. J., Meuwissen S. G., Pena A. S. HLA-DRB1*03, but not the TNFA -308 promoter gene polymorphism, confers protection against fistulising Crohn's disease. Immunogenetics. 1998 May;47(6):451–455. doi: 10.1007/s002510050382. [DOI] [PubMed] [Google Scholar]
  4. Brant S. R., Fu Y., Fields C. T., Baltazar R., Ravenhill G., Pickles M. R., Rohal P. M., Mann J., Kirschner B. S., Jabs E. W. American families with Crohn's disease have strong evidence for linkage to chromosome 16 but not chromosome 12. Gastroenterology. 1998 Nov;115(5):1056–1061. doi: 10.1016/s0016-5085(98)70073-3. [DOI] [PubMed] [Google Scholar]
  5. Brown J. H., Jardetzky T. S., Gorga J. C., Stern L. J., Urban R. G., Strominger J. L., Wiley D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. doi: 10.1038/364033a0. [DOI] [PubMed] [Google Scholar]
  6. Cariappa A., Sands B., Forcione D., Finkelstein D., Podolsky D. K., Pillai S. Analysis of MHC class II DP, DQ and DR alleles in Crohn's disease. Gut. 1998 Aug;43(2):210–215. doi: 10.1136/gut.43.2.210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Caruso C., Oliva L., Palmeri P., Cottone M. B cell alloantigens in Sicilian patients with Crohn's disease. Tissue Antigens. 1983 Feb;21(2):170–172. doi: 10.1111/j.1399-0039.1983.tb00387.x. [DOI] [PubMed] [Google Scholar]
  8. Caruso C., Palmeri P., Oliva L., Orlando A., Cottone M. HLA antigens in ulcerative colitis: a study in the Sicilian population. Tissue Antigens. 1985 Jan;25(1):47–49. doi: 10.1111/j.1399-0039.1985.tb00411.x. [DOI] [PubMed] [Google Scholar]
  9. Cho J. H., Nicolae D. L., Gold L. H., Fields C. T., LaBuda M. C., Rohal P. M., Pickles M. R., Qin L., Fu Y., Mann J. S. 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 U S A. 1998 Jun 23;95(13):7502–7507. doi: 10.1073/pnas.95.13.7502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cottone M., Bunce M., Taylor C. J., Ting A., Jewell D. P. Ulcerative colitis and HLA phenotype. Gut. 1985 Sep;26(9):952–954. doi: 10.1136/gut.26.9.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Curran M. E., Lau K. F., Hampe J., Schreiber S., Bridger S., Macpherson A. J., Cardon L. R., Sakul H., Harris T. J., Stokkers P. Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16. Gastroenterology. 1998 Nov;115(5):1066–1071. doi: 10.1016/s0016-5085(98)70075-7. [DOI] [PubMed] [Google Scholar]
  12. Danzé P. M., Colombel J. F., Jacquot S., Loste M. N., Heresbach D., Ategbo S., Khamassi S., Périchon B., Semana G., Charron D. Association of HLA class II genes with susceptibility to Crohn's disease. Gut. 1996 Jul;39(1):69–72. doi: 10.1136/gut.39.1.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. De La Concha E. G., Fernandez-Arquero M., Santa-Cruz S., Lopez-Nava G., Figueredo M. A., Diaz-Rubio M., Garcia-Paredes J. Positive and negative associations of distinct HLA-DR2 subtypes with ulcerative colitis (UC). Clin Exp Immunol. 1997 Jun;108(3):392–395. doi: 10.1046/j.1365-2249.1997.3951285.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Duerr R. H., Barmada M. M., Zhang L., Davis S., Preston R. A., Chensny L. J., Brown J. L., Ehrlich G. D., Weeks D. E., Aston C. E. Linkage and association between inflammatory bowel disease and a locus on chromosome 12. Am J Hum Genet. 1998 Jul;63(1):95–100. doi: 10.1086/301929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Duerr R. H., Neigut D. A. Molecularly defined HLA-DR2 alleles in ulcerative colitis and an antineutrophil cytoplasmic antibody-positive subgroup. Gastroenterology. 1995 Feb;108(2):423–427. doi: 10.1016/0016-5085(95)90069-1. [DOI] [PubMed] [Google Scholar]
  16. Forcione D. G., Sands B., Isselbacher K. J., Rustgi A., Podolsky D. K., Pillai S. An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele. Proc Natl Acad Sci U S A. 1996 May 14;93(10):5094–5098. doi: 10.1073/pnas.93.10.5094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fujita K., Naito S., Okabe N., Yao T. Immunological studies in Crohn's disease. I. Association with HLA systems in the Japanese. J Clin Lab Immunol. 1984 Jun;14(2):99–102. [PubMed] [Google Scholar]
  18. Futami S., Aoyama N., Honsako Y., Tamura T., Morimoto S., Nakashima T., Ohmoto A., Okano H., Miyamoto M., Inaba H. HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression. Dig Dis Sci. 1995 Apr;40(4):814–818. doi: 10.1007/BF02064985. [DOI] [PubMed] [Google Scholar]
  19. Gorski J., Tilanus M., Giphart M., Mach B. Oligonucleotide genotyping shows that alleles at the HLA-DR beta III locus of the DRw52 supertypic group segregate independently of known DR or Dw specificities. Immunogenetics. 1987;25(2):79–83. doi: 10.1007/BF00364271. [DOI] [PubMed] [Google Scholar]
  20. Green A. The epidemiologic approach to studies of association between HLA and disease. I. The basic measures, concepts and estimation procedures. Tissue Antigens. 1982 Apr;19(4):245–258. doi: 10.1111/j.1399-0039.1982.tb01449.x. [DOI] [PubMed] [Google Scholar]
  21. Green A. The epidemiologic approach to studies of association between HLA and disease. II. Estimation of absolute risks, etiologic and preventive fraction. Tissue Antigens. 1982 Apr;19(4):259–268. doi: 10.1111/j.1399-0039.1982.tb01450.x. [DOI] [PubMed] [Google Scholar]
  22. Heresbach D., Colombel F., Danze P. M., Semana G. The HLA DRB1*0301-DQB1*0201 haplotype confers protection against inflammatory bowel disease. Am J Gastroenterol. 1996 May;91(5):1060–1060. [PubMed] [Google Scholar]
  23. Hesresbach D., Alizadeh M., Bretagne J. F., Gautier A., Quillivic F., Lemarchand B., Gosselin M., Genetet B., Semana G. Investigation of the association of major histocompatibility complex genes, including HLA class I, class II and TAP genes, with clinical forms of Crohn's disease. Eur J Immunogenet. 1996 Apr;23(2):141–151. doi: 10.1111/j.1744-313x.1996.tb00275.x. [DOI] [PubMed] [Google Scholar]
  24. Hugot J. P., Laurent-Puig P., Gower-Rousseau C., Olson J. M., Lee J. C., Beaugerie L., Naom I., Dupas J. L., Van Gossum A., Orholm M. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature. 1996 Feb 29;379(6568):821–823. doi: 10.1038/379821a0. [DOI] [PubMed] [Google Scholar]
  25. Jardetzky T. S., Brown J. H., Gorga J. C., Stern L. J., Urban R. G., Chi Y. I., Stauffacher C., Strominger J. L., Wiley D. C. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature. 1994 Apr 21;368(6473):711–718. doi: 10.1038/368711a0. [DOI] [PubMed] [Google Scholar]
  26. Kobayashi K., Atoh M., Konoeda Y., Yagita A., Inoko H., Sekiguchi S. HLA-DR, DQ and T cell antigen receptor constant beta genes in Japanese patients with ulcerative colitis. Clin Exp Immunol. 1990 Jun;80(3):400–403. doi: 10.1111/j.1365-2249.1990.tb03300.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kobayashi K., Atoh M., Yagita A., Konoeda Y., Inoko H., Ando A., Sekiguchi S. Crohn's disease in the Japanese is associated with the HLA-DRw53. Exp Clin Immunogenet. 1990;7(2):101–108. [PubMed] [Google Scholar]
  28. Leidenius M. H., Koskimies S. A., Kellokumpu I. H., Höckerstedt K. A. HLA antigens in ulcerative colitis and primary sclerosing cholangitis. APMIS. 1995 Jul-Aug;103(7-8):519–524. doi: 10.1111/j.1699-0463.1995.tb01400.x. [DOI] [PubMed] [Google Scholar]
  29. Matake H., Okabe N., Naito S., Yao T. An HLA study on 149 Japanese patients with Crohn's disease. Gastroenterol Jpn. 1992 Aug;27(4):496–501. doi: 10.1007/BF02777785. [DOI] [PubMed] [Google Scholar]
  30. McConnell R. B. Ulcerative colitis--genetic features. Scand J Gastroenterol Suppl. 1983;88:14–16. [PubMed] [Google Scholar]
  31. Mehal W. Z., Lo Y. M., Wordsworth B. P., Neuberger J. M., Hubscher S. C., Fleming K. A., Chapman R. W. HLA DR4 is a marker for rapid disease progression in primary sclerosing cholangitis. Gastroenterology. 1994 Jan;106(1):160–167. doi: 10.1016/s0016-5085(94)95085-7. [DOI] [PubMed] [Google Scholar]
  32. Mirza M. M., Lee J., Teare D., Hugot J. P., Laurent-Puig P., Colombel J. F., Hodgson S. V., Thomas G., Easton D. F., Lennard-Jones J. E. Evidence of linkage of the inflammatory bowel disease susceptibility locus on chromosome 16 (IBD1) to ulcerative colitis. J Med Genet. 1998 Mar;35(3):218–221. doi: 10.1136/jmg.35.3.218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nakajima A., Matsuhashi N., Kodama T., Yazaki Y., Takazoe M., Kimura A. HLA-linked susceptibility and resistance genes in Crohn's disease. Gastroenterology. 1995 Nov;109(5):1462–1467. doi: 10.1016/0016-5085(95)90631-2. [DOI] [PubMed] [Google Scholar]
  34. Nepom G. T., Erlich H. MHC class-II molecules and autoimmunity. Annu Rev Immunol. 1991;9:493–525. doi: 10.1146/annurev.iy.09.040191.002425. [DOI] [PubMed] [Google Scholar]
  35. Peña A. S., Biemond I., Kuiper G., Weterman I. T., van Leeuwen A., Schreuder I., van Rood J. J. HLA antigen distribution and HLA haplotype segregation in Crohn's disease. Tissue Antigens. 1980 Jul;16(1):56–61. doi: 10.1111/j.1399-0039.1980.tb00287.x. [DOI] [PubMed] [Google Scholar]
  36. Purrmann J., Bertrams J., Knapp M., Cleveland S., Hengels K. J., Gemsa R., Strohmeyer G. Gene and haplotype frequencies of HLA antigens in 269 patients with Crohn's disease. Scand J Gastroenterol. 1990 Oct;25(10):981–985. doi: 10.3109/00365529008997623. [DOI] [PubMed] [Google Scholar]
  37. Reinshagen M., Loeliger C., Kuehnl P., Weiss U., Manfras B. J., Adler G., Boehm B. O. HLA class II gene frequencies in Crohn's disease: a population based analysis in Germany. Gut. 1996 Apr;38(4):538–542. doi: 10.1136/gut.38.4.538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Roussomoustakaki M., Satsangi J., Welsh K., Louis E., Fanning G., Targan S., Landers C., Jewell D. P. Genetic markers may predict disease behavior in patients with ulcerative colitis. Gastroenterology. 1997 Jun;112(6):1845–1853. doi: 10.1053/gast.1997.v112.pm9178675. [DOI] [PubMed] [Google Scholar]
  39. Satsangi J., Parkes M., Louis E., Hashimoto L., Kato N., Welsh K., Terwilliger J. D., Lathrop G. M., Bell J. I., Jewell D. P. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet. 1996 Oct;14(2):199–202. doi: 10.1038/ng1096-199. [DOI] [PubMed] [Google Scholar]
  40. Satsangi J., Welsh K. I., Bunce M., Julier C., Farrant J. M., Bell J. I., Jewell D. P. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet. 1996 May 4;347(9010):1212–1217. doi: 10.1016/s0140-6736(96)90734-5. [DOI] [PubMed] [Google Scholar]
  41. Smolen J. S., Gangl A., Polterauer P., Menzel E. J., Mayr W. R. HLA antigens in inflammatory bowel disease. Gastroenterology. 1982 Jan;82(1):34–38. [PubMed] [Google Scholar]
  42. Sugimura K., Asakura H., Mizuki N., Inoue M., Hibi T., Yagita A., Tsuji K., Inoko H. Analysis of genes within the HLA region affecting susceptibility to ulcerative colitis. Hum Immunol. 1993 Feb;36(2):112–118. doi: 10.1016/0198-8859(93)90113-f. [DOI] [PubMed] [Google Scholar]
  43. Toyoda H., Wang S. J., Yang H. Y., Redford A., Magalong D., Tyan D., McElree C. K., Pressman S. R., Shanahan F., Targan S. R. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology. 1993 Mar;104(3):741–748. doi: 10.1016/0016-5085(93)91009-7. [DOI] [PubMed] [Google Scholar]
  44. Wassmuth R., Eastman S., Kockum I., Holmberg E., Starck M., Lindhagen T., Kalden J. R., Lernmark A., Sundkvist G., Lindgren S. HLA DR and DQ RFLP analysis in Crohn's disease. Eur J Immunogenet. 1993 Oct;20(5):429–433. doi: 10.1111/j.1744-313x.1993.tb00162.x. [DOI] [PubMed] [Google Scholar]
  45. Zetterquist H., Broomé U., Einarsson K., Olerup O. HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis. Gut. 1992 Jul;33(7):942–946. doi: 10.1136/gut.33.7.942. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES