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Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility.

Lai OY, Chen H, Michaud HA, Hayashi G, Kuebler PJ, Hultman GK, Ariza ME, Williams MV, Batista MD, Nixon DF, Foerster J, Bowcock AM, Liao W - J. Invest. Dermatol. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.

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.

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Related in: MedlinePlus

Location of human endogenous retrovirus K (HERV-K) sequence adjacent to HLA-C within the MHC region on chromosome 6The PSORS1 susceptibility locus containing one or more psoriasis risk variants has been mapped in various studies to the region between HLA-B and HCG22. Cen: centromeric; Tel: telomeric. Scale at bottom is human reference sequence assembly GRCh37/hg19.
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Figure 1: Location of human endogenous retrovirus K (HERV-K) sequence adjacent to HLA-C within the MHC region on chromosome 6The PSORS1 susceptibility locus containing one or more psoriasis risk variants has been mapped in various studies to the region between HLA-B and HCG22. Cen: centromeric; Tel: telomeric. Scale at bottom is human reference sequence assembly GRCh37/hg19.

Mentions: We were interested in exploring whether the PSORS1 human endogenous retrovirus K (HERV-K) dUTPase, located 32 kb telomeric of HLA-C (Figure 1), might be independently associated with psoriasis. A previous analysis of several hundred psoriasis families identified a strong psoriasis risk haplotype, termed RH1, which localized to a 60 kb region telomeric to HLA-C (Nair et al., 2000) and which harbors the HERV-K dUTPase. A subsequent analysis of the same dataset using a haplotype sharing statistic demonstrated that the HERV-K dUTPase may be a candidate susceptibility gene for psoriasis (Foerster et al., 2005). Most recently, HERV-K dUTPase protein has been shown to stimulate the production of psoriasis-associated Th1/Th17 cytokines in immune cells through interaction with Toll-like receptor 2 (Ariza and Williams, 2011).


Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility.

Lai OY, Chen H, Michaud HA, Hayashi G, Kuebler PJ, Hultman GK, Ariza ME, Williams MV, Batista MD, Nixon DF, Foerster J, Bowcock AM, Liao W - J. Invest. Dermatol. (2012)

Location of human endogenous retrovirus K (HERV-K) sequence adjacent to HLA-C within the MHC region on chromosome 6The PSORS1 susceptibility locus containing one or more psoriasis risk variants has been mapped in various studies to the region between HLA-B and HCG22. Cen: centromeric; Tel: telomeric. Scale at bottom is human reference sequence assembly GRCh37/hg19.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375357&req=5

Figure 1: Location of human endogenous retrovirus K (HERV-K) sequence adjacent to HLA-C within the MHC region on chromosome 6The PSORS1 susceptibility locus containing one or more psoriasis risk variants has been mapped in various studies to the region between HLA-B and HCG22. Cen: centromeric; Tel: telomeric. Scale at bottom is human reference sequence assembly GRCh37/hg19.
Mentions: We were interested in exploring whether the PSORS1 human endogenous retrovirus K (HERV-K) dUTPase, located 32 kb telomeric of HLA-C (Figure 1), might be independently associated with psoriasis. A previous analysis of several hundred psoriasis families identified a strong psoriasis risk haplotype, termed RH1, which localized to a 60 kb region telomeric to HLA-C (Nair et al., 2000) and which harbors the HERV-K dUTPase. A subsequent analysis of the same dataset using a haplotype sharing statistic demonstrated that the HERV-K dUTPase may be a candidate susceptibility gene for psoriasis (Foerster et al., 2005). Most recently, HERV-K dUTPase protein has been shown to stimulate the production of psoriasis-associated Th1/Th17 cytokines in immune cells through interaction with Toll-like receptor 2 (Ariza and Williams, 2011).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.

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.

Show MeSH
Related in: MedlinePlus