GENETICS OF INFLAMMATORY BOWEL-DISEASE

1. The aetiology of the chronic inflammatory bowel diseases, Crohn's d isease and ulcerative colitis, is uncertain. Studies of specific envir onmental factors and immune dysfunction have provided little insight i nto disease pathogenesis. 2. Concordance rates in twin pairs and sibli ngs provide strong evidence that genetic factors are important in dise ase pathogenesis, In Oxford, information was obtained from 433 adult p atients with Crohn's disease. Compared with the prevalence in the gene ral population, the relative risks in siblings of patients with Crohn' s disease calculated from these data were respectively 36.5 for Crohn' s disease, 16.6 for ulcerative colitis and 24.7 for inflammatory bowel disease. 3. Clinical patterns of disease were compared in members of over 250 multiply affected families with inflammatory bowel disease. A high degree of concordance for many characteristics was noted (diseas e type, extent, extra-intestinal manifestations). However, in 77 affec ted parent-child pairs, the median age of onset in the parents was sig nificantly higher than in offspring (P < 0.0001), These data reflect t he results from other studies throughout the world, and are consistent with the phenomenon of genetic anticipation. 4. A detailed study inve stigating the contribution of the major histocompatibility complex was undertaken. Eighty-three affected sibling pairs were involved in a Li nkage analysis study; 348 patients with inflammatory bowel disease and 472 controls were involved in a detailed allelic association study. T hese data provide evidence that the major histocompatibility complex i s an important determinant in ulcerative colitis, but not in Crohn's d isease. 5. Cytokine genes are important candidate genes in inflammator y bowel disease. Allelic association study was performed to investigat e the contribution of the gene encoding the interleukin-1 receptor ant agonist and tumour necrosis factor-alpha. These data do not suggest th at these genes encode important determinants of disease susceptibility in inflammatory bowel disease. 6. A two-stage genome-wide search for susceptibility loci in inflammatory bowel disease was performed involv ing 186 affected sibling pairs. The data provide strong evidence for t he model of Crohn's disease and ulcerative colitis as related polygeni c disorders. Loci on chromosomes 3, 7 and 12 were linked to inflammato ry bowel disease overall, whereas loci on chromosomes 2 and 6 were lin ked only in ulcerative colitis. Linkage with chromosome 16 was noted i n Crohn's disease only. Fine mapping of these susceptibility loci is i n progress, and may lead to gene identification with attendant clinica l benefits.