Skip to main content

Advertisement

SpringerLink
Log in

HLA-DRB1 Alleles May Influence Disease Phenotype in Patients With Inflammatory Bowel Disease: A Critical Reappraisal With Review of the Literature

  • Original Contributions
  • Published:
Diseases of the Colon & Rectum

PURPOSE

The HLA region has been implicated in determining the disease susceptibility or the clinical phenotype of inflammatory bowel disease. The aim of this study was to assess the relation between HLA-DRB1 alleles with the clinical features of Crohn’s disease and ulcerative colitis and the presence of anti-neutrophil cytoplasmic and anti-Saccharomyces cerevisiae antibodies.

METHODS

Blood samples were obtained from 102 Crohn’s disease patients, 114 ulcerative colitis patients, and 264 unrelated healthy controls. Anti-neutrophil cytoplasmics were detected by a standard immunofluorescence method, and anti-Saccharomyces cerevisiaes were examined by an enzyme-linked immunosorbent assay immunoglobulin G/immunoglobulin A commercial assay. HLA-DRB1 typing of 26 alleles was performed by polymerase chain reaction sequence-specific primes. Patients were phenotyped according to gender, disease location, extent, and behavior, surgical resection, need of steroid, and anti-neutrophil cytoplasmic/anti-Saccharomyces cerevisiae status.

RESULTS

As a whole, after applying Bonferroni’s correction for multiple comparisons, no significant association of HLA-DRB1 alleles with Crohn’s disease or ulcerative colitis was found. After stratifying HLA-DRB1 alleles by clinical phenotypes of patients with ulcerative colitis, an excess of DRB1*1309*1320*1325*1329 allele (DR13) was found in conjunction with pancolitis (P < 0.0001), surgical resection (P < 0.0003), and extraintestinal manifestations (P < 0.0001). In Crohn’s disease patients, an excess of DRB1*0304*0305*0307*0309 allele (DR3) was found in those with colonic disease (P < 0.0001) and patients with extraintestinal manifestations (P = 0.0003). This statistical association, however, emerged in only 3 of 114 patients with ulcerative colitis and in 3 of 102 patients with Crohn’s disease. We found no association with the presence of anti-Saccharomyces cerevisiae or anti-neutrophil cytoplasmic.

CONCLUSIONS

Some clinical features of Crohn’s disease and ulcerative colitis may be influenced by specific HLA-DR alleles; in particular, in ulcerative colitis some alleles appear to segregate with more aggressive disease, whereas in Crohn’s disease different alleles cosegregate in patients with colonic disease and extraintestinal manifestations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

To the article

  1. J Rioux M Silveberg M Daly et al. (2000) ArticleTitleGenome wide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci Am J Hum Genet 66 1863–70 Occurrence Handle10.1086/302913 Occurrence Handle1:CAS:528:DC%2BD3cXntV2jurw%3D Occurrence Handle10777714

    Article  CAS  PubMed  Google Scholar 

  2. J Hampe S Schreiber S Shaw et al. (1999) ArticleTitleA genome-wide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort Am J Hum Genet 64 808–16 Occurrence Handle10.1086/302294 Occurrence Handle1:CAS:528:DyaK1MXitFChtL8%3D Occurrence Handle10053016

    Article  CAS  PubMed  Google Scholar 

  3. H Yang SE Plevy K Taylor et al. (1999) ArticleTitleLinkage of Crohn’s disease to the major histocompatibility complex region is detected by multiple non- parametric analyses Gut 44 519–26 Occurrence Handle1:STN:280:DyaK1M7nslajsA%3D%3D Occurrence Handle10075959 Occurrence Handle10.1136/gut.44.4.519

    Article  CAS  PubMed  Google Scholar 

  4. J Hampe S Shaw R Saiz et al. (1999) ArticleTitleLinkage of inflammatory bowel disease to human chromosome 6p Am J Hum Genet 65 1647–55 Occurrence Handle1:CAS:528:DC%2BD3cXjvFemuw%3D%3D Occurrence Handle10577918

    CAS  PubMed  Google Scholar 

  5. M Reinshagen C Loeliger P Kuehnl (1996) ArticleTitleClass II HLA gene frequencies in Crohn’s disease: a population based analysis in Germany Gut 38 538–42 Occurrence Handle1:STN:280:DyaK28zjslWmtg%3D%3D Occurrence Handle8707084

    CAS  PubMed  Google Scholar 

  6. PM Danze JF Colombel S Jacquot et al. (1996) ArticleTitleAssociation of HLA class II genes with susceptibility to Crohn’s disease Gut 39 69–72 Occurrence Handle1:STN:280:DyaK2s%2Fjs1Wltg%3D%3D Occurrence Handle8881812

    CAS  PubMed  Google Scholar 

  7. E Trachtenberg H Yang E Hayes et al. (2000) ArticleTitleHLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations Hum Immunol 61 326–33 Occurrence Handle1:CAS:528:DC%2BD3cXht1KqtLc%3D Occurrence Handle10689124

    CAS  PubMed  Google Scholar 

  8. JP Hugot P Laurent-Puig C Gower-Rousseau et al. (1994) ArticleTitleLinkage analyses of chromosome 6 loci, including HLA, in familial aggregations of Crohn’s disease Am J Med Genet 52 207–13 Occurrence Handle1:STN:280:DyaK2M7gtValtg%3D%3D Occurrence Handle7802010

    CAS  PubMed  Google Scholar 

  9. JP Hugot P Lauring-Puig C Goewer-Rousseau et al. (1996) ArticleTitleMapping of susceptibility locus for Crohn’s disease on chromosome 16 Nature 379 821–2 Occurrence Handle10.1038/379821a0 Occurrence Handle1:CAS:528:DyaK28XhsVWlu7Y%3D Occurrence Handle8587604

    Article  CAS  PubMed  Google Scholar 

  10. J Satsangi M Parkes E Louis et al. (1996) ArticleTitleTwo-stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosome 3, 7, and 12 Nat Genet 14 199–202 Occurrence Handle10.1038/ng1096-199 Occurrence Handle1:CAS:528:DyaK28XmtVKntLc%3D Occurrence Handle8841195

    Article  CAS  PubMed  Google Scholar 

  11. JH Cho DL Nicolae LH Gold et al. (1998) ArticleTitleIdentification 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 95 7502–7 Occurrence Handle1:CAS:528:DyaK1cXktFChur4%3D Occurrence Handle9636179

    CAS  PubMed  Google Scholar 

  12. Y Ma J Ohmen Z Li et al. (1999) ArticleTitleA genome wide search identifies potential new susceptibility loci for Crohn’s disease Inflamm Bowel Dis 5 271–8 Occurrence Handle1:STN:280:DC%2BD3c%2Fks1SrsA%3D%3D Occurrence Handle10579120 Occurrence Handle10.1002/ibd.3780050406

    Article  CAS  PubMed  Google Scholar 

  13. R Duerr M Barmada L Zhang R Pfutzer D Weeks (2000) ArticleTitleHigh density genome-scan in Crohn’s disease shows confirmed linkage to chromosome 14q11-12 Am J Hum Genet 66 1857–62 Occurrence Handle10.1086/302947 Occurrence Handle1:CAS:528:DC%2BD3cXntV2jur8%3D Occurrence Handle10747815

    Article  CAS  PubMed  Google Scholar 

  14. V Annese A Latiano P Bovio et al. (1999) ArticleTitleGenetic analysis on Italian families with inflammatory bowel disease supports linkage to the IBD1 locus: a GISC study Eur J Hum Genet 7 567–73 Occurrence Handle1:CAS:528:DyaK1MXlvVKnsrk%3D Occurrence Handle10439963

    CAS  PubMed  Google Scholar 

  15. Yang H, Rotter JI. Genetics of inflammatory bowel disease. In: Targan SR, Shanahan F, eds. Inflammatory bowel disease: from bench to bedside. Los Angeles: Lippincott Williams & Wilkins, 1994:32–64.

  16. F Perri V Annese A Piepoli et al. (1998) ArticleTitleHLA antigens and pANCA define ulcerative colitis as a genetically heterogenous disorder Ital J Gastroenterol 30 56–61 Occurrence Handle1:STN:280:DyaK1c3nslCqtw%3D%3D

    CAS  Google Scholar 

  17. PC Stokkers PH Reitsma GN Tytgat SJ Deventer Particlevan (1999) ArticleTitleHLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis Gut 45 395–401 Occurrence Handle1:STN:280:DyaK1Mzns12jtg%3D%3D Occurrence Handle10446108 Occurrence Handle10.1136/gut.45.3.395

    Article  CAS  PubMed  Google Scholar 

  18. J Satsangi KI Welsh M Bunce et al. (1996) ArticleTitleContribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease Lancet 347 1212–7 Occurrence Handle1:STN:280:DyaK283gs1CitQ%3D%3D Occurrence Handle8622450

    CAS  PubMed  Google Scholar 

  19. JK Yamamoto-Furusho LF Uscanga G Vargas-Alarcon et al. (2003) ArticleTitleClinical and genetic heterogeneity in Mexican patients with ulcerative colitis Hum Immunol 64 119–23 Occurrence Handle1:CAS:528:DC%2BD38XpvVajur0%3D Occurrence Handle12507822

    CAS  PubMed  Google Scholar 

  20. M Roussomoustakaki J Satsangi K Welsh et al. (1997) ArticleTitleGenetic marker may predict disease behaviour in patients with ulcerative colitis Gastroenterology 112 845–53

    Google Scholar 

  21. G Bouma M Oudkerk Pool JB Crusius et al. (1997) ArticleTitleEvidence 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 109 175–9 Occurrence Handle1:STN:280:DyaK2szmtFyrsg%3D%3D Occurrence Handle9218841

    CAS  PubMed  Google Scholar 

  22. YT Lee JJ Sung P Poon KN Lai PK Li (1998) ArticleTitleAssociation of HLA class-II genes and anti-neutrophil cytoplasmic antibodies in Chinese patients with inflammatory bowel disease Scand J Gastroenterol 33 623–7 Occurrence Handle1:STN:280:DyaK1czjt1aqug%3D%3D Occurrence Handle9669635

    CAS  PubMed  Google Scholar 

  23. FA Ujar N Imeryuz G Saruhan-Direskeneli et al. (1998) ArticleTitleThe distribution of HLA-DRB alleles in ulcerative colitis patients in Turkey Eur J Immunogenet 25 293–6 Occurrence Handle9777329

    PubMed  Google Scholar 

  24. G Bouma AC Poen MA Garzia-Gonzalez et al. (1998) ArticleTitleHLA-DRB1*03, but not TNF-308 promoter gene polymorphism, confers protection against fistulising Crohn’s disease Immunogenetics 47 451–5 Occurrence Handle1:STN:280:DyaK1c3itFWiug%3D%3D Occurrence Handle9553151

    CAS  PubMed  Google Scholar 

  25. J Satsangi CJ Landers KI Welsh K Koss S Targan DP Jewell (1998) ArticleTitleThe presence of anti-neutrophil antibodies reflects clinical and genetic heterogeneity within inflammatory bowel disease Inflamm Bowel Dis 4 18–26 Occurrence Handle1:STN:280:DyaK1c7nslKnuw%3D%3D Occurrence Handle9552224 Occurrence Handle10.1002/ibd.3780040105

    Article  CAS  PubMed  Google Scholar 

  26. G Bouma MA Garcia-Gonzalez BU Meijer et al. (1999) ArticleTitleGenetic marker in clinically well-defined patients with ulcerative colitis Clin Exp Immunol 115 294–300 Occurrence Handle1:STN:280:DyaK1M7jt1alsw%3D%3D Occurrence Handle9933456

    CAS  PubMed  Google Scholar 

  27. C Folwaczny R Zahn G Brunler et al. (1999) ArticleTitleLack of association between HLA-DRB1 alleles of the major histocompatibility complex and p-ANCA status or clinical characteristics in patients with ulcerative colitis Z Gastroenterol 37 133–40 Occurrence Handle1:STN:280:DyaK1M3gs1antg%3D%3D Occurrence Handle10190246

    CAS  PubMed  Google Scholar 

  28. SJ Myung SK Yang HY Jung et al. (2002) ArticleTitleHLA-DRB1*1502 confers susceptibility to ulcerative colitis, but is negatively associated with its intractability: a Korean study Int J Colorectal Dis 17 233–7 Occurrence Handle12073071

    PubMed  Google Scholar 

  29. TR Orchard S Thiyagaraja KI Welsh BP Wordsworth JS Hill Gaston DP Jewell (2000) ArticleTitleClinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease Gastroenterology 118 274–8 Occurrence Handle1:STN:280:DC%2BD3c7hsFGjsw%3D%3D Occurrence Handle10648455

    CAS  PubMed  Google Scholar 

  30. TR Orchard CN Chua T Ahmad H Cheng KI Welsh DP Jewell (2002) ArticleTitleUveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes Gastroenterology 123 714–8 Occurrence Handle12198697

    PubMed  Google Scholar 

  31. D Hesresbach M Alizadeh JF Bretagne et al. (1996) ArticleTitleInvestigation 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 23 141–51 Occurrence Handle1:CAS:528:DyaK28XivFyks7o%3D Occurrence Handle8732477

    CAS  PubMed  Google Scholar 

  32. T Ahmad A Armuzzi M Bunce et al. (2002) ArticleTitleThe molecular classification of the clinical manifestations of Crohn’s disease Gastroenterology 122 854–66 Occurrence Handle1:CAS:528:DC%2BD38XjtFOmtbk%3D Occurrence Handle11910336

    CAS  PubMed  Google Scholar 

  33. M Lombardi G Pirozzi V Luongo et al. (2001) ArticleTitleCrohn’s disease: susceptibility and disease heterogeneity revealed by HLA genotyping Hum Immunol 62 701–4 Occurrence Handle1:CAS:528:DC%2BD3MXksVymurk%3D Occurrence Handle11423176

    CAS  PubMed  Google Scholar 

  34. CM Gelbmann G Rogler M Gierend V Gross J Scholmerich T Andus (2001) ArticleTitleAssociation of HLA-DR genotypes and IL-1ra gene polymorphism with treatment failure of budesonide and disease patterns in Crohn’s disease Eur J Gastroenterol Hepatol 13 1431–7 Occurrence Handle1:CAS:528:DC%2BD38Xlt12jsw%3D%3D Occurrence Handle11742191

    CAS  PubMed  Google Scholar 

  35. JE Lennard-Jones (1989) ArticleTitleClassification of inflammatory bowel disease. Scand J Gastroenterol 24(Suppl 170) 2–6

    Google Scholar 

  36. DK Podolsky (1991) ArticleTitleInflammatory bowel disease N Engl J Med 325 928–37 Occurrence Handle1:STN:280:DyaK3MzltFamsQ%3D%3D Occurrence Handle1881418 Occurrence Handle10.1056/NEJM199109263251306

    Article  CAS  PubMed  Google Scholar 

  37. V Annese A Piepoli A Andriulli et al. (1998) ArticleTitlePolymorphism of motilin gene in patients with Crohn’s disease Dig Dis Sci 43 715–9 Occurrence Handle1:CAS:528:DyaK1cXis1KitL8%3D Occurrence Handle9558024

    CAS  PubMed  Google Scholar 

  38. H Zetterquest O Olerup (1992) ArticleTitleIdentification of the HLA-DRB1*04, DRB1*07 and DRB1*09 alleles by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours Hum Immunol 34 64–74 Occurrence Handle1356957

    PubMed  Google Scholar 

  39. G Lombardi V Annese A Piepoli et al. (2000) ArticleTitleAntineutrophil cytoplasmic antibodies in inflammatory bowel disease: clinical role and review of the literature Dis Colon Rectum 43 999–1007 Occurrence Handle1:STN:280:DC%2BD3czmsFKhsg%3D%3D Occurrence Handle10910250

    CAS  PubMed  Google Scholar 

  40. A Wiik (1989) ArticleTitleDelineation of a standard procedure for indirect immunofluorescence detection of ANCA Acta Pathol Microbiol Immunol Scand 97 12–3

    Google Scholar 

  41. Annese V, Piepoli A, Lombardi G, et al. Anti-Saccharomyces cerevisiae mannan antibodies (ASCA) in inflammatory bowel disease: comparison of different assays and correlation with clinical features. Aliment Pharmacol Ther (in press).

  42. G Campbell (1994) ArticleTitleAdvances in statistical methodology for the evaluation of diagnostic and laboratory tests Stat Med 13 499–508 Occurrence Handle1:STN:280:DyaK2c3psVKlsQ%3D%3D Occurrence Handle8023031

    CAS  PubMed  Google Scholar 

  43. V Annese A Latiano A Andriulli (2003) ArticleTitleGenetics of inflammatory bowel disease. The beginning of the end or the end of the beginning? Dig Liver Dis 35 442–9 Occurrence Handle1:CAS:528:DC%2BD3sXotFKnt7o%3D Occurrence Handle12868683

    CAS  PubMed  Google Scholar 

  44. DK Bonen JH Cho (2003) ArticleTitleThe genetics of inflammatory bowel disease Gastroenterology 124 521–36 Occurrence Handle1:CAS:528:DC%2BD3sXhsFOgs78%3D Occurrence Handle12557156

    CAS  PubMed  Google Scholar 

  45. N Risch (1987) ArticleTitleAssessing the role of HLA-linked and unlinked determinants of disease Am J Hum Genet 40 1–14 Occurrence Handle1:STN:280:DyaL2s7isVygsw%3D%3D Occurrence Handle3468804

    CAS  PubMed  Google Scholar 

To the Invited Commentary

  1. Lechler R, Warrens A. HLA in health and disease. 2nd ed. San Diego: Academic Press, 2000.

  2. WJ Zhang WA Koltun (2001) ArticleTitleGenetic factors in the etiology and potential management of IBD Semin Colon Rectal Surg 12 2–8

    Google Scholar 

  3. N Inoue K Tamura Y Kinouchi et al. (2002) ArticleTitleLack of common NOD2 variants in Japanese patients with Crohn’s disease Gastroenterology 123 86–91 Occurrence Handle1:CAS:528:DC%2BD38Xmt1aiu70%3D Occurrence Handle12105836

    CAS  PubMed  Google Scholar 

  4. QS Guo B Xia Y Jiang Y Qu J Li (2004) ArticleTitleNOD2 3020insC frameshift mutation is not associated with inflammatory bowel disease in Chinese patients of Han nationality World J Gastroenterol 10 1069–71 Occurrence Handle1:CAS:528:DC%2BD2cXjslGhu7k%3D Occurrence Handle15052696

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors thank Miss De Santo Ermelinda, Mr. Corritore Giuseppe, and Miss Latiano Tiziano for their skillful technical support.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Unit of Gastroenterology and Endoscopy, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy

    V. Annese M.D. & A. Piepoli B.D.

  2. Laboratory of Molecular Biology, Unit of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy

    A. Latiano B.D., G. Lombardi M.D., G. Napolitano M.D., N. Caruso M.D., L. Accadia M.D., F. Perri M.D. & A. Andriulli M.D.

  3. Mendel Institute, Rome, Italy

    E. Cocchiara B.M.

Authors
  1. V. Annese M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Piepoli B.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Latiano B.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Lombardi M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Napolitano M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Caruso M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Cocchiara B.M.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Accadia M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. Perri M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. Andriulli M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work has been supported by a grant of the Health Minister (No. GARC0102).

About this article

Cite this article

Annese, V., Piepoli, A., Latiano, A. et al. HLA-DRB1 Alleles May Influence Disease Phenotype in Patients With Inflammatory Bowel Disease: A Critical Reappraisal With Review of the Literature. Dis Colon Rectum 48, 57–65 (2005). https://doi.org/10.1007/s10350-004-0747-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10350-004-0747-0

Key words

Search

Navigation