Association analysis identifies ZNF750 regulatory variants in psoriasis

We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls.We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p < 0.05). We also identified an excess of rare promoter and 5'untranslated region (UTR) variants in psoriasis cases compared to controls (p = 0.041), whereas there was no significant difference in the number of rare coding and rare 3' UTR variants. Using a promoter functional assay in stimulated human primary keratinocytes, we showed that four ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families.Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.Psoriasis is a chronic, inflammatory disorder of the skin affecting 2-4% of the Caucasian population [1]. Clinically, psoriasis is characterized by red, scaly plaques typically favoring the elbows, knees, scalp, umbilicus, and gluteal cleft and may be associated with nail dystrophy and arthritis. Histologically, psoriasis is marked by epidermal hyperplasia, dilated vasculature in the dermal papillae, and the presence of T cell infiltrates. Genome-wide association studies and other genetic investigations of psoriasis have identified at least 18 common variants affecting psoriasis susceptibility [2-9]. However, in aggregate, these common variants only explain a fraction of the heritability in p