Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

Susceptibility to primary sclerosing cholangitis (PSC) is associated with H LA-B8, -DR3, -DR2, and -DR6. It is not established whether these HLA genes or closely linked genes confer the primary disease susceptibility. MICA and MICB genes are found in the class I region between HLA-B and DRB. MICA is expressed in gastrointestinal epithelium and activates gamma delta T cells in the gut. Because PSC is strongly associated with inflammatory bowel dise ase, we investigated whether MICA and MICB contribute to the HLA-associated genetic susceptibility to develop PSC. The study included 130 PSC patients and 306 healthy controls, previously typed for HLA class I and II genes, t yped for 5 MICA and 15 MICB microsatellite alleles. The phenotype frequenci es of MICA5.1 and MICB24 were significantly increased among PSC patients co mpared with controls (90% vs. 74%; odds ratio [OR] = 3.2; P-c = 3 X 10(-3) and 58% vs. 29%; OR = 3.3; P-c < 1 X 10(-7), respectively). When stratified for B8- or DR3-positive and -negative individuals, the association of thes e markers to PSC was no longer evident. However, we observed that B8 and DR 3 were associated to PSC only in the presence of both MICA5.1 and MICB24 ma rkers. The frequency of individuals carrying all 4 alleles was significantl y increased among the PSC patients compared with controls (49% vs. 18%; OR = 4.5; P-c < 1 X 10(-7)). Our data indicate that PSC is associated to the e xtended B8-MICA5.1-MICB24-DR3 haplotype.