FAMILIAL OCCURRENCE AND INHERITANCE STUDIES IN INFLAMMATORY BOWEL-DISEASE

A number of studies have demonstrated aggregation of cases of ulcerati ve colitis or Crohn's disease in families, and of cases of both diseas es within the same families, suggesting that patients share a genetic background. Perhaps because of differences in the selection of patient s, study design and diagnostic criteria, different patterns of occurre nce of inflammatory bowel disease (IBD) have been found among relative s of patients with these disorders. In recent years, however, several studies have been carried out, aiming by epidemiological methods to re veal(1) the frequency of familial occurrence of IBD among patients wit h ulcerative colitis and Crohn's disease, and (2) the prevalence of IB D among 1(0) relatives to patients with these diseases. Results from t hese studies show a relatively uniform pattern of family occurrence in about 10% of patients with ulcerative colitis and Crohn's disease, an d a prevalence among 1(0) relatives of about 10 times that of the back ground population. A twin study reported a significantly higher concor dance rate for Crohn's disease than for ulcerative colitis in monozygo tic twins. By use of complex segregation analyses in 3 different studi es, a very similar model of inheritance was found to fit for ulcerativ e colitis, namely a major dominant or additive gene with a low penetra nce. For Crohn's disease the best-fitting model was a major recessive gene, with a high penetrance. This difference strongly supports the co ncept of ulcerative colitis and Crohn's disease as two separate diseas e entities. The occurrence of both diseases within the same families i n certain members of the affected families is difficult to explain. Th e search for distinct associations of HLA genes with inflammatory bowe l disease has shown a positive correlation between DR2 and ulcerative colitis and a negative association with DR4 and DRw6, compared with et hnically matched controls. In contrast, in Crohn's disease a positive association with the combination of DR1 and DQw5 alleles was revealed, thus indicating genetically different disease susceptibility for the two disorders. In general, however, no consistent pattern has been rev ealed from studies of association of HLA-A or -B antigens or blood gro up and serum protein markers. In two French families with several memb ers affected with Crohn's disease no evidence for an HLA haplotype ass ociation could be revealed. Possible inherited markers of ulcerative c olitis or Crohn's disease have been sought but without convincing succ ess. Increased intestinal permeability, presence of anticolon antibodi es and presence of antineutrophil leukocyte antibodies have been propo sed, but not proved. Thorough studies are now needed of multimember fa milies with disease for linkage studies to identify loci which contrib ute to increased liability. Such studies are in progress in different centres.