Previous genetic and functional studies have implicated the human endogenous retrovirus K (HERV-K)
dUTPase located within the PSORS1 locus in the major histocompatibility complex region as a candidate
psoriasis gene. Here, we describe a variant discovery and case-control association study of HERV-K
dUTPase variants in 708
psoriasis cases and 349 healthy controls. Five common HERV-K
dUTPase variants were found to be highly associated with
psoriasis, with the strongest association occurring at the missense single-nucleotide polymorphism (SNP) rs3134774 (K158R, P=3.28 × 10(-15), odds ratio =2.36 (95% confidence interval: 1.91-2.92)). After adjusting the association of the HERV-K
dUTPase variants for the potential confounding effects of HLA alleles associated with
psoriasis, the HERV-K SNPs rs9264082 and rs3134774 remained significantly associated. Haplotype analysis revealed that HERV-K haplotypes containing the non-risk alleles for rs3134774 and rs9264082 significantly reduced the risk of
psoriasis. Functional testing showed higher antibody responses against recombinant HERV-K
dUTPase in
psoriasis patients compared with controls (P<0.05), as well as higher T-cell responses against a single HERV-K
dUTPase peptide (P<0.05). Our data support an independent role for the HERV-K
dUTPase on
psoriasis susceptibility, and suggest the need for additional studies to clarify the role of this
dUTPase in the pathogenesis of
psoriasis.