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

• Published in: The Journal of clinical investigation Vol. 92; no. 2; pp. 1080 - 1084
• Main Authors: HUIYING YANG, ROTTER, J. I, TOYODA, H, LANDERS, C, TYAN, D, MCELREE, C. K, TARGAN, S. R
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01.08.1993
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Autoantibodies - blood; Biological and medical sciences; Biomarkers - blood; Colitis, Ulcerative - blood; Colitis, Ulcerative - genetics; Colitis, Ulcerative - immunology; DNA - blood; DNA - genetics; DNA - isolation & purification; Enzyme-Linked Immunosorbent Assay; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes, MHC Class I; Genes, MHC Class II; Genetic Markers; Histocompatibility Testing; HLA-DQ Antigens - blood; HLA-DQ Antigens - genetics; HLA-DR Antigens - blood; HLA-DR Antigens - genetics; Humans; Leukocytes - immunology; Male; Medical sciences; Middle Aged; Neutrophils - immunology; Other diseases. Semiology; Reference Values; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Human; HLA-System; Pathophysiology; Antibody; Granulocyte; Autoantibody; Inflammatory disease; Crohn disease; Digestive diseases; Genetics; Intestinal disease; Neutrophil; Ulcerative colitis
• ISSN: 0021-9738; 1558-8238
• 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.