title: Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (antineutrophil cytoplasmic antibodies) markers.
abstract: 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.
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
authors.forename: H
authors.initials: H
authors.lastname: Toyoda
authors.forename: C
authors.initials: C
authors.lastname: Landers
authors.forename: D
authors.initials: D
authors.lastname: Tyran
authors.forename: C K
authors.initials: CK
authors.lastname: McElree
authors.forename: S R
authors.initials: SR
authors.lastname: Targan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003093:Colitis, Ulcerative / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D005819:Genetic Markers; D006683:HLA-DQ Antigens / Q000097:blood / Q000235:genetics; D006684:HLA-DR Antigens / Q000097:blood / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D007962:Leukocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology*; D012016:Reference Values
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D005819:Genetic Markers; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D004247:DNA