Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (antineutrophil cytoplasmic antibodies) markers.
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.
Yang
H
H
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Rotter
J I
JI
Toyoda
H
H
Landers
C
C
Tyran
D
D
McElree
C K
CK
Targan
S R
SR
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
D001323:Autoantibodies; D015415:Biomarkers; D005819:Genetic Markers; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D004247:DNA