Genetic heterogeneity within ulcerative colitis determined by an interleukin-1 receptor antagonist gene polymorphism and antineutrophil cytoplasmic antibodies

Background Although there is strong evidence implicating genetic predisposi tion in the pathogenesis of the chronic inflammatory bowel diseases, the nu mber and identity of susceptibility genes remain uncertain. Cytokine genes are tentative candidate loci, but data regarding association studies in dif ferent populations are conflicting. Aims To determine potential associations of interleukin-1 receptor antagoni st (IL-1ra), tumour necrosis factor alpha (TNF alpha), and tumour necrosis factor beta (TNF beta) gene polymorphisms with ulcerative colitis or subset s of ulcerative colitis in a Spanish population. Methods Genotyping for IL-1ra, TNF alpha and TNF beta gene polymorphisms wa s performed by the polymerase chain reaction in 95 patients with ulcerative colitis and 74 healthy controls. A variable number of tandem repeats (VNTR ) in the IL-1ra gene, and a single base pair polymorphism in the TNF alpha gene promoter region (-308) and in the first intron of the TNF beta gene we re analysed. Anti-neutrophil cytoplasmic antibodies (ANCA) were detected us ing an indirect immunofluorescence assay. Results There were no significant differences between ulcerative colitis pa tients and controls in either polymorphism analysed, nor between ulcerative colitis subgroups as a function of the clinical disease pattern. However, when stratified by their ANCA status, perinuclear ANCA (p-ANCA) ulcerative colitis showed an increased frequency of the genotype 1,2 of the IL-1ra gen e compared with ANCA-negative ulcerative colitis (52% versus 28%; P = 0.02, P-corr = 0.1). Furthermore, p-ANCA ulcerative colitis had a statistically significant increase of this genotype compared with cytoplasmic ANCA (c-ANC A)/ANCA-negative ulcerative colitis (52% versus 26.5%; P = 0.01, P-corr = 0 .05). Conclusions In the Spanish population studied, the polymorphisms analysed i n the IL-1ra, TNF alpha and TNF beta genes are unlikely to be important in the overall susceptibility to ulcerative colitis. However, the combination of a subclinical (p-ANCA) and a genetic (IL-1ra gene) marker identified a d istinct ulcerative colitis subgroup (p-ANCA; IL-1ra genotype 1,2). These fi ndings provide further evidence of genetic heterogeneity within ulcerative colitis, and support the concept that ANCA may represent a subclinical mark er of genetic heterogeneity. Eur J Gastroenterol Hepatol 11:413-420 (C) 199 9 Lippincott Williams & Wilkins.