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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.
AuthorsOlivia Y Lai, Haoyan Chen, Henri-Alexandre Michaud, Genki Hayashi, Peter J Kuebler, Gustaf K Hultman, Maria-Eugenia Ariza, Marshall V Williams, Mariana D Batista, Douglas F Nixon, John Foerster, Anne M Bowcock, Wilson Liao
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 132 Issue 7 Pg. 1833-40 (Jul 2012) ISSN: 1523-1747 [Electronic] United States
PMID22437317 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • HLA-C Antigens
  • Pyrophosphatases
  • dUTP pyrophosphatase
Topics
  • Alleles
  • B-Lymphocytes (immunology)
  • Case-Control Studies
  • Disease Susceptibility
  • Endogenous Retroviruses (enzymology, genetics)
  • HLA-C Antigens (genetics)
  • Haplotypes
  • Humans
  • Polymorphism, Single Nucleotide
  • Psoriasis (etiology)
  • Pyrophosphatases (physiology)
  • T-Lymphocytes (immunology)

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