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 predisposition in the pathogenesis of the chronic inflammatory bowel diseases, the number and identity of susceptibility genes remain uncertain. Cytokine genes are tentative candidate loci, but data regarding association studies in different populations are conflicting. Aims To determine potential associations of interleukin-1 receptor antagonist (IL-1 ra), tumour necrosis factor α (TNFα), and tumour necrosis factor (TNFβ) gene polymorphisms with ulcerative colitis or subsets of ulcerative colitis in a Spanish population. Methods Genotyping for IL-1 ra, TNFα and TNFβ gene polymorphisms was 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 TNFα gene promoter region (-308) and in the first intron of the TNFβ gene were analysed. Anti-neutrophil cytoplasmic antibodies (ANCA) were detected using an indirect immunofluorescence assay. Results There were no significant differences between ulcerative colitis patients 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 gene 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-ANCA)/ ANCA-negative ulcerative colitis (52% versus 26.5%; P = 0.01, P corr = 0.05). Conclusions In the Spanish population studied, the polymorphisms analysed in the IL-1ra, TNFα and TNFβ 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-1 ra gene) marker identified a distinct ulcerative colitis subgroup (p-ANCA; IL-1 ra genotype 1,2). These findings provide further evidence of genetic heterogeneity within ulcerative colitis, and support the concept that ANCA may represent a subclinical marker of genetic heterogeneity.