Comparison of MHC class I risk haplotypes in Thai and Caucasian psoriatics shows locus heterogeneity at PSORS1

Earlier studies have shown that psoriasis in Japan and Thailand is associated with two different major histocompatibility complex (MHC) haplotypes - those bearing HLA-Cw6 and those bearing HLA-Cw1 and HLA-B46. In an independent case-control sample from Thailand, we confirmed the association of psoriasis with both haplotypes. No association was seen in Thai HLA-Cw1 haplotypes lacking HLA-B46, nor was HLA-Cw1 associated with psoriasis in a large Caucasian sample. To assess whether these risk haplotypes share a common origin, we sequenced genomic DNA from a Thai HLA-Cw1-B46 homozygote across the similar to 300 kb MHC risk interval, and compared it with sequence of a HLA-Cw6-B57 risk haplotype. Three small regions of homology were found, but these regions share equivalent sequence similarity with one or more clearly non-risk haplotypes, and they contain no polymorphism alleles unique to all risk haplotypes. Differences in psoriasis phenotype were also observed, including lower risk of disease, greater nail involvement, and later age at onset in HLA-Cw1-B46 carriers compared with HLA-Cw6 carriers. These findings suggest locus heterogeneity at PSORS1 (psoriasis susceptibility 1), the major psoriasis susceptibility locus in the MHC, with HLA-Cw6 imparting risk in both Caucasians and Asians, and an allele other than HLA-Cw1 on the HLA-Cw1-B46 haplotype acting as an additional risk variant in East Asians.