CONTRIBUTION OF GENES OF THE MAJOR HISTOCOMPATIBILITY COMPLEX TO SUSCEPTIBILITY AND DISEASE PHENOTYPE IN INFLAMMATORY BOWEL-DISEASE

Background Despite strong evidence implicating immune dysfunction and genetic predisposition in the pathogenesis of the chronic inflammatory bower diseases Crohn's disease and ulcerative colitis, the importance of the genes of the major histocompatibility complex remains uncertai n, We have investigated the contribution of HLA DRB1 and DQB genes by the strategies of non-parametric linkage analysis (affected sibling pa ir method) as well as association study. The relation between genotype and phenotype was examined in detail. Methods For linkage analysis 74 families in whom two or more siblings had inflammatory bowel disease were studied. A total of 83 affected sibling pairs were involved: in 4 2 pairs both siblings had Crohn's disease; in 29 both had ulcerative c olitis; in 12 one sibling had Crohn's disease, the other ulcerative co litis. for the association study there were 175 patients with ulcerati ve colitis, 173 with Crohn's disease, and 472 controls. Details of sex , age of onset, disease extent, and family history were analysed. 24 p atients with ulcerative colitis and 92 with Crohn's disease required s urgery for refractory disease, HLA DRB1 and DQB1 gene-typing was perfo rmed by polymerase chain reaction with sequence-specific primers. Find ings in ulcerative colitis, the sharing of alleles among affected sibl ing pairs provided evidence for linkage with DRB1 locus (p=0 . 017, ch i(2)=5 . 32). Of 29 affected sibling pairs studied, only one pair shar ed no DRB1 DQB haplotypes. 15 shared two DRB DQB haplotypes. In contra st, no linkage was noted for Crohn's disease (42 sibling pairs; p=0 . 30, chi 2=0 . 16) or for inflammatory bowel disease overall (83 siblin g pairs, p=0 . 16, chi(2)=2 . 28), In the association study the rare D RB1103 (8 . 3% vs 3 . 2% in controls) and DRB1*12 (8 . 6% vs 2 . 1% i n controls) alleles were associated with ulcerative colitis (p=0 . 007 4, chi(2)=7 . 22, odds ratio OR=2 . 9 [95% CI 1 . 3-6-4] and p=0 . 005 6, chi(2)=12 . 63, OR=4 . 33 [1 . 8-11 . 0] respectively). No associat ion with alleles representing DR2 (p=0 . 55, chi(2)=0 . 34) was noted, No overall association was seen in Crohn's disease, In ulcerative col itis, the frequency of DRB10301 DQB*0201 (DR3 DQ2) was reduced in fem ales (9 . 8% vs 26 . 3% in controls, p=0 . 037, chi(2)=8 . 39 OR=0 . 3 4 (0 . 15-0 . 71]), particularly in those with distal disease (2 . 3%, p=0 . 001 vs controls, chi(2)=11 . 35, OR=0 . 07 [0 . 00-0 . 39]). In both males and females, the DR3 DQ2 haplotype was predictive of exten sive ulcerative colitis (32 . 9% vs 10 . 7% in distal disease, p<0 . 0 1, chi(2)=10 . 94, OR 4 . 09 [1 . 70-10 . 6]) but not of need for surg ery (p=0 . 93, chi(2)=0 . 01), Interpretation These data provide stron g evidence for genetic heterogeneity in inflammatory bower disease. Ge nes of the major histocompatibility complex are implicated as importan t inherited determinants of susceptibility to ulcerative colitis and m ay also influence the pattern of disease. In Crohn's disease, importan t susceptibility genes are likely to exist outside the HLA region.