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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

IgG antibody responses against recombinant HERV-K dUTPaseThe response against HERV-K dUTPase was screened using 23 psoriasis patient and 16 healthy donor serum samples at a 1:800 dilution. The human dUTPase was used as a control. Psoriasis subjects had a greater humoral response against HERV-K dUTPase compared to the healthy blood donors. No response against the human dUTPase was detected even at the lowest dilution used (data not shown). * p<0.05, Mann-Whitney U test.
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Figure 3: IgG antibody responses against recombinant HERV-K dUTPaseThe response against HERV-K dUTPase was screened using 23 psoriasis patient and 16 healthy donor serum samples at a 1:800 dilution. The human dUTPase was used as a control. Psoriasis subjects had a greater humoral response against HERV-K dUTPase compared to the healthy blood donors. No response against the human dUTPase was detected even at the lowest dilution used (data not shown). * p<0.05, Mann-Whitney U test.

Mentions: To determine whether HERV-K dUTPase protein elicits humoral responses, we tested sera from 23 psoriasis patients and 16 healthy donors for responses to recombinant wild-type HERV-K dUTPase. As shown in Figure 3, psoriasis subjects had a greater humoral response against HERV-K dUTPase compared to the healthy blood donors (p=0.0334, Mann-Whitney U test). No response was observed against vehicle control or against human dUTPase control protein even at the lowest dilution used (data not shown). Our data suggest that certain epitopes in the HERV-K dUTPase protein may be eliciting an immunological response in psoriasis patients. Future studies examining the specificity of the antibody response against the high-risk and low-risk dUTPase proteins as defined by our genetic analysis are warranted.


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)

IgG antibody responses against recombinant HERV-K dUTPaseThe response against HERV-K dUTPase was screened using 23 psoriasis patient and 16 healthy donor serum samples at a 1:800 dilution. The human dUTPase was used as a control. Psoriasis subjects had a greater humoral response against HERV-K dUTPase compared to the healthy blood donors. No response against the human dUTPase was detected even at the lowest dilution used (data not shown). * p<0.05, Mann-Whitney U test.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: IgG antibody responses against recombinant HERV-K dUTPaseThe response against HERV-K dUTPase was screened using 23 psoriasis patient and 16 healthy donor serum samples at a 1:800 dilution. The human dUTPase was used as a control. Psoriasis subjects had a greater humoral response against HERV-K dUTPase compared to the healthy blood donors. No response against the human dUTPase was detected even at the lowest dilution used (data not shown). * p<0.05, Mann-Whitney U test.
Mentions: To determine whether HERV-K dUTPase protein elicits humoral responses, we tested sera from 23 psoriasis patients and 16 healthy donors for responses to recombinant wild-type HERV-K dUTPase. As shown in Figure 3, psoriasis subjects had a greater humoral response against HERV-K dUTPase compared to the healthy blood donors (p=0.0334, Mann-Whitney U test). No response was observed against vehicle control or against human dUTPase control protein even at the lowest dilution used (data not shown). Our data suggest that certain epitopes in the HERV-K dUTPase protein may be eliciting an immunological response in psoriasis patients. Future studies examining the specificity of the antibody response against the high-risk and low-risk dUTPase proteins as defined by our genetic analysis are warranted.

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