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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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Linkage disequilibrium plot for HLA-C*06:02, HLA-B*57:01, and HERV-K dUTPase SNPsr2 values between pairs of SNPs are shown.
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Figure 2: Linkage disequilibrium plot for HLA-C*06:02, HLA-B*57:01, and HERV-K dUTPase SNPsr2 values between pairs of SNPs are shown.

Mentions: We sequenced a 431 bp genomic fragment of the PSORS1 HERV-K dUTPase in 708 Caucasian psoriasis cases and 349 Caucasian controls. Previous sequencing of a larger 4.2 kb region around the dUTPase showed that the 431 bp fragment contained the variants associated with high-risk and low-risk psoriasis haplotypes (Foerster et al., 2005). The 431 bp fragment encompasses the C-terminal portion of the dUTPase protein starting at consensus amino acid 108 and includes dUTPase domains 3, 4, and 5. We identified a total of 14 DNA variants, 9 of which were novel and rare (MAF<5%) (Table 1). We then conducted association testing of the identified HERV variants with psoriasis using logistic regression, adjusting the results for potential population stratification using a panel of 87 European ancestry informative markers. We found that all five common (MAF>5%) HERV-K dUTPase polymorphisms were highly associated with psoriasis (p < 10-4, exceeding the Bonferroni threshold of 0.05/14=0.0036, Table 1). The HERV-K SNP most highly associated with psoriasis was rs3134774, an A/G polymorphism corresponding to the non-synonymous change K158R (p=3.28 × 10-15, OR=2.36). rs3134774 was in nearly perfect linkage disequilibrium (LD) with the non-coding SNP rs3134775 (r2=0.99 in our dataset) and in high LD with the non-coding SNP rs3132531 (r2=0.83) (Figure 2). The synonymous HERV-K SNP rs9264082, which was in low LD with rs3134774 (r2=0.16), was associated with psoriasis protection (p=1.68 × 10-9, OR=0.50), as was the non-synonymous SNP rs114780460 (p=2.98 × 10-5, OR=0.59). Although none of the nine rare HERV-K variants (MAF<5%) demonstrated statistical association with psoriasis, as would be expected from power limitations, we did note that rare variant NOVEL8 encoding the non-synonymous change D166G was seen in 4 psoriasis cases and none of the controls (Table 1).


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)

Linkage disequilibrium plot for HLA-C*06:02, HLA-B*57:01, and HERV-K dUTPase SNPsr2 values between pairs of SNPs are shown.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Linkage disequilibrium plot for HLA-C*06:02, HLA-B*57:01, and HERV-K dUTPase SNPsr2 values between pairs of SNPs are shown.
Mentions: We sequenced a 431 bp genomic fragment of the PSORS1 HERV-K dUTPase in 708 Caucasian psoriasis cases and 349 Caucasian controls. Previous sequencing of a larger 4.2 kb region around the dUTPase showed that the 431 bp fragment contained the variants associated with high-risk and low-risk psoriasis haplotypes (Foerster et al., 2005). The 431 bp fragment encompasses the C-terminal portion of the dUTPase protein starting at consensus amino acid 108 and includes dUTPase domains 3, 4, and 5. We identified a total of 14 DNA variants, 9 of which were novel and rare (MAF<5%) (Table 1). We then conducted association testing of the identified HERV variants with psoriasis using logistic regression, adjusting the results for potential population stratification using a panel of 87 European ancestry informative markers. We found that all five common (MAF>5%) HERV-K dUTPase polymorphisms were highly associated with psoriasis (p < 10-4, exceeding the Bonferroni threshold of 0.05/14=0.0036, Table 1). The HERV-K SNP most highly associated with psoriasis was rs3134774, an A/G polymorphism corresponding to the non-synonymous change K158R (p=3.28 × 10-15, OR=2.36). rs3134774 was in nearly perfect linkage disequilibrium (LD) with the non-coding SNP rs3134775 (r2=0.99 in our dataset) and in high LD with the non-coding SNP rs3132531 (r2=0.83) (Figure 2). The synonymous HERV-K SNP rs9264082, which was in low LD with rs3134774 (r2=0.16), was associated with psoriasis protection (p=1.68 × 10-9, OR=0.50), as was the non-synonymous SNP rs114780460 (p=2.98 × 10-5, OR=0.59). Although none of the nine rare HERV-K variants (MAF<5%) demonstrated statistical association with psoriasis, as would be expected from power limitations, we did note that rare variant NOVEL8 encoding the non-synonymous change D166G was seen in 4 psoriasis cases and none of the controls (Table 1).

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