Psoriasis Vulgaris Susceptibility Research Articles

Association Study of the Caspase Gene Family and Psoriasis Vulgaris Susceptibility in Northeastern China.

Background Abnormal apoptosis of keratinocytes is one of the pathological changes of psoriasis. Caspases (CASPs) are the central engines of apoptosis. Studies to date have shown that some SNPs alter the expression of related genes and lead to changes in disease risk. However, no studies have investigated the associations between gene polymorphisms and the risk of psoriasis in Han population in northeast China. Therefore, we conducted a case-control study to explore this question in Han population of northeastern China. Methods 540 patients with PsV and 612 healthy age- and sex-matched controls were enrolled in this study. We determined the genotypes of 17 single nucleotide polymorphisms (SNPs) from 11 genes of caspase family by the improved multiplex ligation detection reaction (iMLDR) method. A model-based single SNP frequentist test and haplotype association studies were performed to evaluate the association between SNPs and PsV. Results In the single SNP tests, rs6704688 in CASP8 was significantly associated with psoriasis vulgaris (PsV) in Han population of northeastern China (P = 0.0169, P' = 0.0179 under the additive model; P = 0.0126, P' = 0.0149 under the heterozygous model). In haplotype analyses, the CASP7 haplotype GC was found to be associated with PsV risk (case group versus control group, 47.2% versus 54.4%, respectively, p = 0.0149). Conclusions Our study presented that the gene polymorphisms of CASP7 and CASP8 were significantly associated with PsV in Han population of northeastern China, which implied the functional relationship between PsV and caspase genes. CASP8 and CASP7 SNPs could be new potential biomarkers for risk stratification and prevention of PsV.

Association of ERAP1 gene polymorphisms with the susceptibility to psoriasis vulgaris: A case-control study.

Psoriasis vulgaris (PsV), also known as plaque psoriasis, is a life-threatening autoimmune skin disease. Inflammatory factors may contribute to the development of PsV. Present study aimed to explore the association of endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms (rs26653 and rs27524) with PsV susceptibility in a Chinese Han population. Subgroup analysis was also performed based on the onset of PsV.Present case–control study included 143 patients with PsV and 149 healthy controls. Direct sequencing method was used for genotyping ERAP1 polymorphisms. Chi-squared test was used to estimate the association between ERAP1 polymorphisms and PsV susceptibility. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess association strength.The polymorphism rs26653 was positively correlated with PsV susceptibility (CC vs GG, P = .047, OR = 1.964, 95% CI = 1.006–3.834; C vs G, P = .042, OR = 1.403, 95% CI = 1.011–1.946). Meanwhile, its CC genotype and C allele were positively associated with the early onset of PsV (P = .036, OR = 2.080, 95% CI = 1.044–4.145; P = .034, OR = 1.443, 95% CI = 1.028–2.024) and increased PsV risk in the subgroup with family history (P = .029, OR = 2.149, 95% CI = 1.075–4.296; P = .027, OR = 1.466, 95% CI = 1.044–2.059).ERAP1 gene rs26653 polymorphism may increase the risk of PsV in Chinese Han population.

Association of NLRP1 and NLRP3 Polymorphisms with Psoriasis Vulgaris Risk in the Chinese Han Population.

Aim To clarify the association between the single nucleotide polymorphisms (SNPs) in the NLRP1 and NLRP3 and Psoriasis Vulgaris (PsV) in the Chinese Han population. Methods We genotyped eight SNPs, four from NLRP1 (rs8079034, rs11651270, rs11657747, and rs878329) and NLRP3 (rs7512998, rs3806265, rs10754557, and rs10733113) each in 540 patients with PsV and 612 healthy controls in the Chinese Han population using an improved multiplexed ligation detection reaction (iMLDR) method. The genotype and haplotype frequencies were analyzed using a case-control study design. Results We identified two SNPs, rs3806265 and rs10754557, in NLRP3 that were significantly associated with PsV. The genotype distribution of the rs3806265 SNP was significantly different between cases and controls (p = 0.0451; OR = 0.791; 95% CI = 0.627–0.998). In the recessive model, the genotype distribution of the rs10754557 SNP was significantly different between cases and controls (p = 0.0344; OR = 1.277; 95% CI = 0.987–1.652). The haplotype analysis of rs3806265 and rs10754557 also presented a significant association of TA haplotype with PsV (χ2 = 4.529; p = 0.033). Conclusion NLRP3 may play a role in PsV susceptibility in the Chinese Han population.

MMP-9 gene polymorphisms (rs3918242, rs3918254 and rs4810482) and the risk of psoriasis vulgaris: No evidence for associations in a Chinese Han population

Several previous studies including one of them co-authored by our group have revealed that serum and psoriatic plaque expression of matrix metalloproteinase-9 (MMP-9) was significantly upregulated in psoriasis. The aim of this study was to investigate the association of three single nucleotide polymorphisms (SNPs) and haplotypes of MMP-9 (rs3918242, rs3918254 and rs4810482) with psoriasis vulgaris in a Chinese Han population. The serum levels of MMP-9 in 245 psoriasis vulgaris cases and 256 healthy controls were assessed using ELSA kits, and the three SNPs were genotyped using polymerase chain reaction–ligation detection reaction (PCR-LDR) method. Four haplotypes based on the three SNPs were also analyzed. Our study showed that the serum MMP-9 levels in patients with psoriasis vulgaris were significantly higher than that in controls (P<0.05). However, the three SNPs were not significantly associated with psoriasis vulgaris susceptibility (all P>0.05). Similar results were found in further subgroup analysis based on gender, age of onset, family history, and serum MMP-9 levels, except that a protective effect of psoriasis vulgaris was detected among female subjects with the CT genotype of rs3918254 (OR=0.47, 95% CI=0.23-0.96, P=0.038), but this association did not survive after Bonferroni correction (Padj=0.076). The haplotype analysis also failed to show any association with psoriasis vulgaris. We found no evidence for the association between the MMP-9 polymorphisms and psoriasis vulgaris susceptibility in a Chinese Han population.

Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes

Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C∗06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10−364). Stepwise analysis revealed multiple HLA-C∗06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C∗12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10−8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10−11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

IL36RN Mutations in Generalized Pustular Psoriasis: Just the Tip of the Iceberg?

As IL36RN mutations are a cause of generalized pustular psoriasis (GPP), three recent investigations attempted to correlate the IL36RN genotype with GPP clinical presentations. These studies found that IL36RN mutations account for only a fraction of GPP cases presenting with concomitant psoriasis vulgaris (PV; common or typical psoriasis). Pathogenic alleles were also found in control populations, indicating that environmental triggers and/or modifier genes may contribute to the disease.

Genome-Wide Meta-Analysis of Psoriatic Arthritis Identifies Susceptibility Locus at REL

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25% to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 SNPs were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18×10−8, OR=1.27, 95% CI=1.18–1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3 and NFκBIA.

Genetic susceptibility factors for psoriatic arthritis

Psoriatic arthritis (PsA) has a large genetic component to its heritability, yet investigation into the genetic basis of the disease has lagged behind other rheumatic diseases mainly because of the difficulty in defining classification criteria that would accurately differentiate it from other forms of inflammatory arthritis. However, using a variety of approaches, some confirmed associations have now been identified with PsA susceptibility, making a review of these recent developments timely. Family studies continue to suggest a large genetic contribution to PsA. Using a candidate gene approach, genes robustly confirmed to be associated with psoriasis vulgaris (PsV) have also been found to be associated with PsA (HLA-Cw*0602, IL23R, IL12B). There is less overlap reported with rheumatoid arthritis (RA) than PsV susceptibility loci but one report suggests that the AFF3 locus may be associated with both RA and PsA. Large, well powered genome-wide association studies are currently underway and should provide further insights into the cause of this common arthritic disease over the next few months. The bulk of evidence so far suggests that the genetic factors underlying PsV are also associated with PsA suggesting that future studies of PsV could include patients with PsA.

Genetic polymorphisms of the HCR gene and a genomic segment in close proximity to HLA-C are associated with patients with psoriasis in Taiwan

Although psoriasis vulgaris (PV) is strongly associated with HLA-Cw*0602, it has been proposed that the association of Cw*0602 is due to linkage disequilibrium and that other nearby genes are involved in PV susceptibility. The alpha-helix coiled-coil rod homologue (HCR) gene, located 110 kb telomeric to the HLA-C locus, is presumed to be one of the PV candidate genes. Recently, a 10-kb genomic segment, centromeric to HLA-C, defined by two new single nucleotide polymorphisms (SNPs) n.7*A and n.9*C, was found to have a stronger association with psoriasis than the HCR gene. Until now, no study of the association of the HCR gene, SNPs n.7, and n.9 has been conducted on Chinese patients with psoriasis. We aimed to determine whether the genetic polymorphisms of the HCR gene, SNPs n.7*A, and n.9*C were associated with an increased risk of psoriasis in Chinese patients. Using direct sequencing of the HCR gene and the genomic region containing SNPs n.7 and n.9, we investigated the HCR gene, SNPs n.7, and n.9 for disease association in 115 Chinese patients with psoriasis and 103 control subjects. The HCR SNPs were confirmed by denaturing high performance liquid chromatography. Genotyping for HLA-Cw*0602 was also carried out using sequence-based typing. We observed a different allelic distribution between patient and control groups at nucleotide positions 386, 404, 1802 and 2406 of the HCR gene, and SNPs n.7, and n.9. The associations were much stronger in early onset PV patients (for HCR-386*T and HCR-404*T, odds ratio = 5.63, Pc < 0.0001). The HLA-Cw*0602 also displayed a similar association with PV (odds ratio = 5.4, Pc < 0.0001). Moreover, SNP n.7*A, SNP n.9*C, Cw*0602, HCR-386*T, HCR-404*T and HCR-1802*T were in linkage disequilibrium with each other. Haplotype-based association analysis showed SNP n.7*A-SNP n.9*C-Cw*0602-HCR-386*T-HCR-404*T-HCR-1802*T-HCR-2406*G as a major susceptibility haplotype in this Chinese population (for early onset patients, odds ratio = 5.15, Pc < 0.0001). Our results indicate that the HCR gene, SNP n.7*A, and SNP n.9*C as well as Cw*0602 are major susceptibility markers for psoriasis in Chinese patients.

SPR1 gene near HLA-C is unlikely to be a psoriasis susceptibility gene.

Although genetics analyses have identified the HLA-Cw6 allele to be the major risk allele for psoriasis vulgaris (PV) in many racial groups, it has been proposed that other putative genes near the HLA-C locus are involved in PV susceptibility and that the association of Cw6 is a result of linkage disequilibrium. The SPR1 gene, a predicted gene located 128 kb telomeric to the HLA-C locus, is considered to be one potential candidate gene of PV. Until now, no association study of the SPR1 gene has been conducted on psoriasis patients. We investigated the SPR1 gene for disease association by direct sequencing of the SPR1 gene in 116 Chinese patients with PV and 116 normal subjects. Genotyping for HLA-Cw6 was also carried out using polymerase chain reaction/restriction fragment length polymorphism. Significant increase of the HLA-Cw6 allele was found in psoriasis patients (32.8% vs. 13.8%, P = 0.001). We found that the SPR1 gene is a highly polymorphic gene containing 13 single nucleotide polymorphisms (SNPs), two of which have not been previously reported, and four SNPs cause amino acid change. No significantly different allelic distribution of 13 SPR1 SNPs could be found between the patients with PV and controls after correction for multiple testing. If the frequencies of SPR1 SNPs were compared between the early onset psoriatics and control subjects, early onset patients were more likely to have G allele at position 988 (60% vs. 35.3%, P = 0.001). However, the significance disappeared upon stratification for the Cw6 status. Haplotype-based association analysis showed two susceptibility haplotypes (types 8 and 19) in early onset psoriasis patients. Nonetheless, the significance also disappeared after stratification of the Cw6 status. Our results suggest that HLA-Cw6 remains the major risk allele in Chinese psoriatics, and that the SPR1 gene might not play an important role in the causation of PV.

Linkage disequilibrium analysis of familial psoriasis: identification of multiple disease-associated MHC haplotypes.

Although psoriasis vulgaris (PsV) is strongly associated with certain human leukocyte antigens, the pathogenetic nature of these associations remains elusive. The objectives of this study were: (i) to determine whether HLA loci directly determine susceptibility or merely serve as markers for the susceptibility allele; and (ii) to identify additional disease-associated haplotypes. By applying maximum likelihood linkage disequilibrium analysis (LDA) in cases vs. controls, we found the susceptibility gene to be more strongly associated with specific HLA haplotypes than with their component alleles. Stronger linkage disequilibrium between PsV and HLA alleles was detected at HLA-C and HLA-B than at DRB1 and DQB1. Parametric linkage analysis accounting for marker-trait disequilibrium in psoriasis vulgaris pedigrees yielded most significant results for a locus close to HLA-B and -C. Furthermore, we found that susceptibility is linked to at least three different ancestral HLA haplotypes; among them, HLA-Cw7-B8-DRB1*0301-DQB1*02 is linked to PsV for the first time. These results identify a major PsV susceptibility locus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and suggest that multiple disease alleles have arisen during human evolution.