Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: The role of MICA polymorphism

Background & Aims: Recent studies suggest that major histocompatibility com plex-encoded susceptibility to primary sclerosing cholangitis (PSC) maps to the HLA B-TNFA region on chromosome 6p21.3, Methods: The present study use s a standard polymerase chain reaction protocol to investigate the 16 commo n alleles of the MICA locus as candidates in 2 patient populations (King's College Hospital, London, and John Radcliffe Hospital, Oxford). Results: Th e MICA*002 allele was found in 4 of 62 (6.4%) patients and none of 50 patie nts vs. 41 of 118 (35%) controls (pc = 0.00018, odds ratio [OR] = 0.12, and P = 0.0000016, OR = 0.0, respectively). Overall, the MICA*008 allele was m ore common in PSC (gene frequency 66% vs. 48% of controls, P = 0.0023, OR = 2.11), However, unlike MICA*002 in which the difference was a result of th e absence of MICA*002 heterozygotes, the MICA*008 association may be caused by an increased frequency of MICA*008 homozygosity in patients (58% vs. 22 %, pc = 0.000015, OR = 5.01 and 58% vs. 22%, P = 0.0000056, OR = 4.51, resp ectively). Though MICA*008 is found on the ancestral 8.1 haplotype, stratif ication analysis indicates that this association is independent of B8 and o ther HLA haplotypes associated with PSC. Conclusions: The MICA*002 allele h as a strong dominant effect in reducing the risk of PSC, whereas the increa sed risk of disease associated with MICA*008 may be a recessive effect requ iring 2 copies of the MICA*008 allele.