title: Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility.
abstract: 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.
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Olivia Y
authors.initials: OY
authors.lastname: Lai
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.forename: Henri-Alexandre
authors.initials: HA
authors.lastname: Michaud
authors.forename: Genki
authors.initials: G
authors.lastname: Hayashi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kuebler
authors.forename: Gustaf K
authors.initials: GK
authors.lastname: Hultman
authors.forename: Maria-Eugenia
authors.initials: ME
authors.lastname: Ariza
authors.forename: Marshall V
authors.initials: MV
authors.lastname: Williams
authors.forename: Mariana D
authors.initials: MD
authors.lastname: Batista
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: John
authors.initials: J
authors.lastname: Foerster
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.forename: Wilson
authors.initials: W
authors.lastname: Liao
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D004198:Disease Susceptibility; D020077:Endogenous Retroviruses / Q000201:enzymology* / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000209:etiology*; D011755:Pyrophosphatases / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015236:HLA-C Antigens; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase