Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families

Abstract:  A susceptibility locus for psoriasis, PSORS4, has been mapped to chromosome 1q21 in the region of the epidermal differentiation complex. The region has been refined to a 115 kb interval around the loricrin (LOR) gene. However, no evidence of association between polymorphisms in the LOR gene and psoriasis has been found. Therefore, we have analysed association to three candidate gene clusters of the region, the S100, small proline-rich protein (SPRR) and PGLYRP (peptidoglycan recognition protein) genes, which all contain functionally interesting psoriasis candidate genes. In previous studies, the SPRR and S100 genes have shown altered expression in psoriasis. Also polymorphisms in the PGLYRP genes have shown to be associated with psoriasis. We genotyped altogether 29 single nucleotide polymorphisms (SNPs) in 255 Finnish psoriasis families and analysed association with psoriasis using transmission disequilibrium test. A five-SNP haplotype of PGLYRP SNPs associated significantly with psoriasis. There was also suggestive evidence of association to SPRR gene locus in Finnish families. To confirm the putative associations, selected SNPs were genotyped also in a family collection of Swedish and Irish patients. The families supported association to the two gene regions, but there was also evidence of allelic heterogeneity.     

Systematic linkage disequilibrium analysis of SLC12A8 at PSORS5 confirms a role in susceptibility to psoriasis vulgaris

The gene for solute carrier family 12 member A8 has recently been proposed as a candidate gene for psoriasis susceptibility (PSORS5) on chromosome 3q based on association of five single nucleotide polymorphisms (SNP) in Swedish patients. To investigate whether this locus is relevant for German psoriasis vulgaris (PsV) patients, we analyzed a group of 210 trios and a case-control group including 375 patients. Based on our investigation of the linkage disequilibrium (LD) structure of SLC12A8, we assayed 35 haplotype tag SNP and grouped them into nine LD-blocks. In the case-control study, we detected an association for six SNP and three LD-based haplotypes. Association was strongest for ss35527511 (chi2 = 11.224, p = 0.0008) and haplotype E-2 (chi2 = 11.788, p = 0.00059) and independent of the presence of an HLA-associated PSORS1 risk allele. Through extended haplotype analysis, we could show that two independent association signals exist in SLC12A8, suggesting allelic heterogeneity. None of the SNP showed association in trios, apart from a weak association of rs2228674 (transmission disequilibrium test statistics p = 0.048), probably due to insufficient power. We conclude that SLC12A8 is a susceptibility locus for PsV. In order to establish the exact nature of this association, efforts to identify the disease-causing variants are ongoing.     

Fine mapping of the psoriasis susceptibility gene PSORS1: a reassessment of risk associated with a putative risk haplotype lacking HLA-Cw6

Human leukocyte antigen (HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLA-Cw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case-control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.     

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.     

The major psoriasis susceptibility locus PSORS1 is not a risk factor for late-onset psoriasis

PSORS1 is the major susceptibility locus for psoriasis vulgaris (PV) and lies within an approximately 200 kb segment of the major histocompatibility complex on chromosome 6p21.3. Alleles of candidate genes in this region including human leukocyte antigen (HLA)-C, alpha-helical coiled coil rod (HCR), and corneodesmosin (CDSN) show association with early-onset PV. Late-onset psoriasis (LOP) is defined as a disease with onset after 40 y of age and is typically sporadic. We assessed the role of PSORS1 in genetic susceptibility to LOP. Genotyping for HLA-C alleles and seven single nucleotide polymorphisms (SNP) within the genes HCR and CDSN was performed in LOP (n=145) and normal controls (n=309). Statistical analysis of allelic frequencies included calculation of odds ratio and chi2 comparisons. LOP demonstrated only a weak association to PSORS1 alleles HLA-Cw*6 (p=0.037), CDSN*5 (p=0.041), HCR*WC (p=0.013), and HCR SNP +325 (p=0.038). Patients with age of onset for psoriasis of 50 y or above provided no evidence of association with any of these alleles. These data suggest that the study cohort may include a number of subjects who harbor PSORS1 predisposition to early-onset psoriasis and yet do not present with disease by the age of 40 y. Thus this study demonstrates that PSORS1 is not a major inherited risk factor in the pathogenesis of LOP. These data suggest that the exclusion of LOP subjects from case-control studies will aid further delineation of the PSORS1 locus. Future genome-wide studies will be required to identify loci conferring risk for late-onset disease.     

Haplotype sharing analysis identifies a retroviral dUTPase as candidate susceptibility gene for psoriasis

The psoriasis susceptibility locus 1 (PSORS1) mutation is assumed to reside within a region around human leukocyte antigen-C spanning 250 kb, termed risk haplotype (RH) 1/2. By re-analyzing a published data set with a previously developed method, the haplotype sharing statistic, we confirm localization of PSORS1 to the RH1 region and refine its location to marker M6S168. We replicate this result in an independent patient sample. The target region harbors fragments of a human endogenous retrovirus K (HERV-K) endogenous retrovirus. Two single-nucleotide polymorphisms with alleles differing between high- and low-risk haplotypes are located within the HERV-K dUTPase. One of these encodes a predicted non-conserved Glu-Arg exchange. The HERV-K dUTPase is expressed in peripheral blood and in normal as well as lesional psoriatic skin. Our results indicate that an endogenous retroviral dUTPase constitutes a candidate gene for the PSORS1 mutation.     

Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes

BACKGROUND: Besides the HLA-Cw*0602 allele, the psoriasis susceptibility 1 candidate 3 (PSORS1C3) and corneodesmosin (CDSN) genes are two probable psoriasis susceptibility genes in the PSORS1 locus. The -79C, -26C and +246A alleles of the PSORS1C3 gene, the CDSN*971T allele, CDSN*TTC (619T-1236T-1243C) and CDSN*5 (619T-1240G-1243C) are strongly associated with psoriasis in the caucasian population. Until now, no haplotype study of the PSORS1C3 and CDSN genes has been documented in Chinese patients with psoriasis vulgaris. OBJECTIVES: We aimed to determine whether genetic polymorphisms of the PSORS1C3 and CDSN genes were associated with an increased risk of psoriasis vulgaris in Chinese patients in Taiwan. METHODS: We investigated the PSORS1C3 and CDSN genes for disease association by direct sequencing in 178 patients with psoriasis vulgaris and 203 control subjects. Genotyping for HLA-Cw*0602, alpha-helix coiled-coil rod homologue (HCR) gene and single nucleotide polymorphism (SNP) n.9 was also carried out using a sequence-based typing method. RESULTS: The PSORS1C3*582A allele, an SNP in the 3'-untranslated region of the PSORS1C3 gene, was a major psoriasis vulgaris susceptibility allele in the Chinese population, and the association was much stronger in patients with early-onset psoriasis vulgaris (22.3% vs. 6.9%, odds ratio = 3.87, P(c) =0.0000072). The frequencies of CDSN*TTC and CDSN*971T were also significantly increased in patients with early-onset psoriasis vulgaris. Moreover, PSORS1C3*582A, SNP n.9*C, Cw*0602 and HCR*WWCC were in near complete linkage disequilibrium (LD) with each other; in contrast, the LD with the CDSN gene was not so strong. SNP n.9*C-Cw*0602-PSORS1C3*582A-HCR*WWCC was a major susceptibility haplotype in patients with early-onset psoriasis vulgaris (P < 10(-7)) and this risk haplotype also carried CDSN*TTC and CDSN*971T. CONCLUSIONS: The PSORS1C3 and CDSN genes are important psoriasis susceptibility genes in Chinese patients with psoriasis vulgaris.     

Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population

Through a series of linkage analyses in a large Chinese family cohort of psoriasis, we previously identified and confirmed a non-HLA psoriasis linkage locus PSORS9 within a small region at 4q31.2-32.1. Within the critical region of the PSORS9 locus, IL-15 has been long recognized as a strong candidate gene for psoriasis. In this study, we investigated the association between IL-15 genetic polymorphisms and psoriasis in a large Chinese sample. Highly significant evidence for association was identified at a single-nucleotide polymorphism (SNP) (g.96516A --> T) within the 3'-untranslated region (UTR) of the IL-15 gene (P=0.00006, after correction for multiple testing). Haplotype analysis using the SNPs within the 3'UTR region also provided strong supporting evidence for association (P=0.00005), where we identified a haplotype of the 3'UTR region of IL-15 associated with increased risk to psoriasis (odds ratio=1.65). This association was also supported by the results of our expression activity analyses, where we demonstrated that the identified risk haplotype is associated with an increased activity of IL-15. Therefore, we provided early evidence for the important role of IL-15 genetic variants in the pathogenesis of psoriasis, probably by increasing interleukin production and inflammation in the lesions of psoriasis.     

Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1

The major susceptibility locus for psoriasis, PSORS1, resides on chromosome 6p and includes the candidate genes HLA-C, HCR, and CDSN. Based on a nationwide collection of psoriasis patients and genotyping for the PSORS1 susceptibility haplotype, we selected for a genome scan nine families who do not show association with PSORS1 to more easily detect minor loci for psoriasis susceptibility. In the genome scan, five loci gave initial evidence of linkage and were studied with a denser marker map. After fine mapping, only one locus on 18p11.23 showed suggestive evidence of linkage (nonparametric multipoint linkage analysis score, 3.58; p = 0.0038). The bootstrapping analysis showed that one large family contributed the majority of the linkage (p = 0.0039), but was supported by other families. Haplotype sharing between the linked families and haplotype association analysis gave additional support for the locus. Further, the 18p locus has shown nominal evidence of linkage with psoriasis in the British population. Taken together, these findings confirm the presence of a minor susceptibility locus for psoriasis on 18p11.     

A study of PSORS1C1 gene polymorphisms in Chinese patients with psoriasis

BACKGROUND: Although genetic analyses have identified the HLA-Cw*0602 allele as the major risk allele for chronic plaque psoriasis in various ethnic groups, it has been proposed that the association of Cw*0602 is due to linkage disequilibrium and that other nearby genes are involved in susceptibility to psoriasis. The psoriasis susceptibility 1 candidate 1 (PSORS1C1, formerly SEEK1) gene, located 127 kb telomeric to the HLA-C locus, is considered to be one of the potential candidate genes of psoriasis. Up to the present, no association study of the PSORS1C1 gene has been conducted on Chinese patients with psoriasis. OBJECTIVES: We aimed to determine whether the genetic polymorphisms of the PSORS1C1 gene were associated with an increased risk of psoriasis in Chinese patients. METHODS: We investigated the PSORS1C1 gene for disease association by direct sequencing of the PSORS1C1 gene in 143 Chinese patients with chronic plaque psoriasis and 188 control subjects. Genotyping for HLA-Cw*0602 and the alpha-helix coiled-coil rod homologue (C6orf18, formerly HCR) gene was also carried out using a sequence-based typing method. RESULTS: We identified 10 single nucleotide polymorphisms (SNPs) on the PSORS1C1 gene in our subjects; four of these SNPs cause amino acid change. We also detected poly(C) repeat variants from nucleotide positions 386-392 (poly(C)6-8). The poly(C) repeat polymorphisms cause a frame shift mutation. Another poly(C) repeat variant was also found at nucleotide positions 748-751. No significantly different allelic distributions of the PSORS1C1 SNPs or poly(C) repeat polymorphisms could be found between the patients with chronic plaque psoriasis and controls after correction for multiple testing. However, a significant increase of the Cw*0602 allele and tryptophan-tryptophan allele of the C6orf18 gene (HCR*WW) was found in patients with early onset psoriasis (21.9% vs. 4.8%, P < 10(-7)). Haplotype-based association analysis also showed a susceptibility haplotype carrying Cw*0602 and HCR*WW alleles in early onset Chinese patients. CONCLUSIONS: Our results indicate that the PSORS1C1 gene might not play an important role in the causation of chronic plaque psoriasis in Chinese people.     

Investigation of the chromosome 17q25 PSORS2 locus in atopic dermatitis

Psoriasis and atopic dermatitis (AD) are strongly genetic and inherited as multi-factorial traits. In both diseases, linkage has been reported to chromosome 17q25. For psoriasis, the locus has been labelled PSORS2. Two peaks of association here contain the psoriasis candidate genes SLC9A3R (solute carrier family 9, isoform 3 regulatory factor), NAT9 (N-acetyltransferase superfamily), and RAPTOR (rapamycin (TOR)). We genotyped 14 of the most significantly associated single-nucleotide polymorphisms (SNPs) in these genes in a panel of 148 families (ECZ1) identified through a proband with active AD. The panel contains 350 siblings and 245 sib-pairs. Replication of positive findings was sought in a second panel, MRC-E, comprising of 278 families, 634 siblings, and 470 sib-pairs. SNP genotyping was carried out by Sequenom MassArray technology. Using family-based tests of association (transmission disequilibrium test), rs878906, in intron 3 of NAT9, was significantly associated with AD (P = 0.010) in the ECZ1 panel. In the MRC-E panel, rs895691, between the end of exon 6 of SLC9A3R1 and exon 7 of NAT9, was associated with AD (P = 0.037). These were not significant when multiple comparisons were taken into account. Haplotype analysis revealed no significant associations in either population. These results suggest that the psoriasis candidate genes do not account for previously observed linkage of the 17q25 PSORS2 locus to AD.     

Association of skin barrier genes within the PSORS4 locus is enriched in Singaporean Chinese with early-onset psoriasis

Psoriasis (OMIM#177900) is a common polygenic skin disorder affecting approximately 2% of the northern European population and 0.1% of the Han Chinese. Psoriasis patients suffer from chronic skin inflammation, manifested by erythematous scaly lesions. PSORS1-PSORS9 have been confirmed as psoriasis susceptibility loci in independent genetic studies on predominantly Caucasian populations, with psoriasis susceptibility loci (PSORS1, PSORS9) and additional loci at 9q33-34 and 2p22.3-11.2 reported in Han Chinese patients. In this study, we show the association of PSORS4 with psoriasis in Singaporean Chinese. Dense genotyping of single-nucleotide polymorphism-tagging candidate genes within the epidermal differentiation complex revealed significant association in the proximity of the involucrin gene (IVL); the strongest association was seen in early-onset psoriasis patients (P=0.0014). A follow-up genome-wide association screen localized the psoriasis susceptibility region to approximately 360 kb along chromosome 1 in the vicinity of IVL, small proline-rich region (SPRR) and proline-rich region 9 (PRR9) genes. The study of interactions between the causative variant(s) in this locus will provide insights into a possible role for epidermal barrier formation in the pathogenesis of psoriasis.     

HLA-Cw*0602 associates more strongly to psoriasis in the Swedish population than variants of the novel 6p21.3 gene PSORS1C3

The PSORS1 locus in the major histocompatibility complex region on chromosome 6p21.3 contains a major predisposing factor for psoriasis for which several candidate genes have been tested. The analyses are complicated by strong linkage disequilibrium in the region and the complex genetic background of psoriasis. In the search for an alternative to HLA-C we have identified a novel gene, PSORS1C3, and characterized it with regard to psoriasis. PSORS1C3 is located approximately 7 kb centromeric to POU5F1. A putative protein of 58 amino acids was predicted and expression was detected in both normal and psoriasis skin. Sequencing of the coding region revealed a total of 11 single nucleotide polymorphisms. When comparing the frequencies of PSORS1C3 variants in a case-control material in the Swedish population, three single nucleotide polymorphisms displayed significant association with psoriasis. This association appeared to be HLA-Cw*0602-dependent due to linkage disequilibrium, thus HLA-C remains the strongest associating factor in the region.     

Genome‐wide linkage scan for psoriasis susceptibility loci in multiplex Tunisian families

Background Psoriasis is a relapsing chronic inflammatory skin disease affecting all population groups, with a peak prevalence of 3% in northern European and Scandinavian caucasians. Epidemiological studies have implicated a genetic component to psoriasis. In the past 12 years multiple genome‐wide linkage analyses have identified putative susceptibility loci on several chromosomes, with a major locus in the major histocompatibility complex region. Objectives To investigate the genetic basis of familial psoriasis in the Tunisian population using a genome‐wide linkage scan in seven multiplex psoriatic families from Tunisia. Methods Following single nucleotide polymorphism (SNP) genotyping on the Affymetrix 10K SNP array, we performed nonparametric linkage (NPL) multipoint analyses to identify genotypes and obtain evidence for linkage with psoriasis across the genome. Results No chromosomal region gave consistent evidence for linkage, providing evidence for genetic heterogeneity in Tunisian psoriasis families. Significant evidence for linkage of psoriasis to chromosome 2p12 was seen in one family. We also identified several regions of tentative psoriasis linkage on chromosomes 2q, 4q, 6p, 11q, 12q, 9q and 13q. One family exhibiting suggestive evidence for linkage to 17q25 (PSORS2) was identified and all affected members harboured a p.Gly117Ser mutation in CARD14 (caspase recruitment domain family, member 14), recently reported to lead to psoriasis in a large family from the U.S.A. Conclusions Our results support the genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2.     

The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene

The PSORS1 locus in the human major histocompatibility complex on 6p21 has been consistently associated with psoriasis in populations of diverse ethnicity. The HLA-C allele Cw*0602, located therein, has been found in up to 67% of psoriasis patients but is no longer considered a candidate gene in itself. The alpha-helix coiled-coil rod homolog gene (HCR, previously Pg8) is located 110 kb from the HLA-C gene, positioned between the CDSN and SC1 genes, within a region thought to harbor a psoriasis gene (PSORS1). We investigated the HCR gene for disease association by direct sequencing of nine polymerase chain reaction products amplified from a series of Swedish psoriasis patients and controls. We found that HCR is a very polymorphic gene with 25 polymorphisms in the open reading frame alone, of which 10 demonstrated disease association; however, the relationship between HCR polymorphisms and HLA-Cw*0602 indicates that HCR cannot truly be considered a likely candidate gene. We investigated Cw*0602 association while stratifying for HCR single nucleotide polymorphisms. We also investigated HCR single nucleotide polymorphism association with the disease while stratifying for the presence of Cw*0602. We found that whichever single nucleotide polymorphism that was stratified for, there was still a strongly significant Cw*0602 association with psoriasis; however, when we stratified for Cw*0602 presence, only one silent polymorphism showed significant association. In a recent similar study this polymorphism was actually found to be decreased in psoriasis individuals. Thus we conclude that HCR polymorphisms display association with psoriasis due to linkage disequilibrium with Cw*0602 and is, therefore, unlikely to be directly involved in the development of psoriasis.     

Association scan of the novel psoriasis susceptibility region on chromosome 19: evidence for both susceptible and protective loci

To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.     

Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations

PSORS1 on chromosome 6p21.3, which contains the MHC, is a major susceptibility locus for psoriasis vulgaris. This region is characterized by strong linkage disequilibrium and contains the corneodesmosin (CSDN) gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility. We compared two genetically independent populations in order to define the major psoriasis susceptibility gene, a British Caucasian population comprising parent-offspring trios analysed by the transmission disequilibrium test (TDT) and a Japanese case-control population. All individuals were investigated for CDSN polymorphism (+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G, +1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition defines this region further by identifying a high-risk CDSN haplotype (allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was observed in the Japanese cohort for any HLA-C or CDSN alleles. This data supports a role for the CDSN gene in Caucasian populations with psoriasis. However the lack of association with HLA-Cw6 and CDSN alleles in Japanese psoriasis patients may be because Japanese patients exhibit a form of psoriasis similar to late onset or Type II psoriasis vulgaris in contrast to early onset or Type I disease characterizing our Caucasian population.     

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

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.