Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis

Abstract

Psoriasis is a common, chronic, inflammatory skin disorder. A number of genetic loci have been shown to confer risk for psoriasis. Collectively, these offer an integrated model for the inherited basis for susceptibility to psoriasis that combines altered skin barrier func tion together with the dysregulation of innate immune pathogen sensing and adaptive immunity. The major histocompatibility complex (MHC) harbours the psoria- sis susceptibility region which exhibits the largest effect size, driven in part by variation contained on the HLA-Cw ? 0602 allele. However, the resolution of the number and genomic location of potential independent risk loci are hampered by extensive linkage disequilibrium across the region. We leveraged the power of large psoriasis case and control data sets and the statistical approach of conditional analysis to identify potential further association signals distribut ed across the MHC. In addition to the major loci at HLA-C ( P 5 2.20 3 10 2 236 ), we observed and replicated four additional independent signals for disease association, three of which are novel. We detected evidence for association at SNPs rs2507971 ( P 5 6.73 3 10 2 14 ), rs9260313 ( P 5 7.93 3 10 2 09 ), rs66609536 ( P 5 3.54 3 10 2 07 ) and rs380924 ( P 5 6.24 3 10 2 06 ), located within the class I region of the MHC, with each observation replicated in an independent sample ( P ? 0.01). The pre- viously identified locus is close to MICA , the other three lie near MICB , HLA-A and HCG9 (a non-coding RNA gene). The identification of disease associations with both MICA and MICB is particularly intriguing, since each encodes an MHC class I-related protein with potent immunological function