Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (antineutrophil cytoplasmic antibodies) markers

J Clin Invest. 1993 Aug;92(2):1080-4. doi: 10.1172/JCI116613.


Newly described distinct associations of HLA class II genes with ulcerative colitis (UC) (DR2) and Crohn's disease (CD) (DR1/DQ5) provide strong evidence for genetic heterogeneity of susceptibility between these two forms of inflammatory bowel disease. A familial distribution of antineutrophil cytoplasmic antibodies (ANCAs, a subclinical marker of UC) in UC families has further implied the existence of heterogeneity within UC. To test the hypothesis that the heterogeneity within UC indicated by ANCAs has a genetic basis that resides within the HLA region, we studied 89 UC cases and an ethnically matched control group (n = 50). Serological and molecular typing techniques were applied to define HLA class II genes (DR, DQ). ANCAs were detected using an enzyme-linked immunosorbent assay, and positive values were confirmed by indirect immunofluorescence. We observed that ANCA-positive UC patients (n = 70) had a significantly increased frequency of DR2 compared with ANCA-negative controls (n = 46) (44% vs 22%, P = 0.01). In contrast, the frequency of DR2 in ANCA-negative UC cases (21%) was virtually identical to that in controls (22%, P = 0.9). Furthermore, the ANCA-negative UC patients had an increase in the DR4 allele compared with ANCA-positive UC (P = 0.004). Thus, with the combination of a subclinical marker (ANCAs) and molecular genetic markers, genetic heterogeneity has been demonstrated within UC: ANCA-positive UC associated with DR2, and ANCA-negative UC likely associated with DR4.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Autoantibodies / blood*
  • Biomarkers / blood
  • Colitis, Ulcerative / blood
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / immunology*
  • DNA / blood
  • DNA / genetics
  • DNA / isolation & purification
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genes, MHC Class I*
  • Genes, MHC Class II*
  • Genetic Markers
  • HLA-DQ Antigens / blood
  • HLA-DQ Antigens / genetics
  • HLA-DR Antigens / blood
  • HLA-DR Antigens / genetics
  • Histocompatibility Testing
  • Humans
  • Leukocytes / immunology
  • Male
  • Middle Aged
  • Neutrophils / immunology*
  • Reference Values


  • Autoantibodies
  • Biomarkers
  • Genetic Markers
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • DNA