Psoriasis Susceptibility Research Articles

2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells.

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.

Fine mapping and subphenotyping implicates ADRA1B gene variants in psoriasis susceptibility in a Chinese population.

A genomic region on 5q33.3 lies between and encompasses the IL12B and PTTG1 genes, and contains many potential psoriasis causal variants. We aimed to further examine the influence of variants in and around this region. We used least absolute shrinkage and selection operator (LASSO)-based regression analysis to assess independent contributions of 2171 variants to psoriasis susceptibility and tested them for association with different clinical psoriasis subtypes. We found that ADRA1B gene variants contribute to psoriasis in Chinese population. ADRA1B gene variants have a stronger association with moderate-to-severe disease group and an earlier age at onset of psoriasis than IL-12B and PTTG1 variants. The association of variants in the ADRA1B gene with psoriasis could explain why variants in the IL-12B, ADRA1B and PTTG1 gene regions are associated with psoriasis.

Association of rs2910164 polymorphism in MiR-146a gene with psoriasis susceptibility: A meta-analysis.

The rs2910164 single nucleotide polymorphism (SNP) in miR-146a has been implicated in the etiology of psoriasis in different relevant studies with contradictory conclusions and limited sample size. Therefore, the aim of this study was to undertake a systematic review and meta-analysis to estimate the association between rs2910164 SNP and psoriasis. We searched the databases of PubMed, EMBASE, Web of Science, WanFang, and Chinese National Knowledge Infrastructure (CNKI) to identify relevant literatures published before July 15, 2018. Four case–control studies including 2212 cases and 2274 healthy controls from 4 different countries met the predetermined criteria. The effect size was pooled by odds ratios (ORs) and 95% confidence intervals (95%CIs). Recessive model (CC vs CG+GG) was confirmed to be the optimal model. The results indicated that rs2910164 SNP was significantly associated with psoriasis (OR = 0.74, 95%CI 0.60–0.91, P = .004), and individuals with CC-genotype were predisposed to have decreased risk of psoriasis.

Multi-omics integration reveals molecular networks and regulators of psoriasis

BackgroundPsoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have been carried out to identify genetic and epigenetic variants that are associated with psoriasis. However, these loci cannot fully explain the disease pathogenesis.MethodsTo achieve a comprehensive mechanistic understanding of psoriasis, we conducted a systems biology study, integrating multi-omics datasets including GWAS, EWAS, tissue-specific transcriptome, expression quantitative trait loci (eQTLs), gene networks, and biological pathways to identify the key genes, processes, and networks that are genetically and epigenetically associated with psoriasis risk.ResultsThis integrative genomics study identified both well-characterized (e.g., the IL17 pathway in both GWAS and EWAS) and novel biological processes (e.g., the branched chain amino acid catabolism process in GWAS and the platelet and coagulation pathway in EWAS) involved in psoriasis. Finally, by utilizing tissue-specific gene regulatory networks, we unraveled the interactions among the psoriasis-associated genes and pathways in a tissue-specific manner and detected potential key regulatory genes in the psoriasis networks.ConclusionsThe integration and convergence of multi-omics signals provide deeper and comprehensive insights into the biological mechanisms associated with psoriasis susceptibility.

IL28RA inhibits human epidermal keratinocyte proliferation by inhibiting cell cycle progression.

Interleukin (IL) 28 receptor α (IL28RA) is a well-known candidate for psoriasis susceptibility based on previous genome-wide association study (GWAS) analysis. However, the function of IL28RA in psoriasis has not been elucidated. In the present study, the expression of IL28RA was significantly decreased in lesional tissues from patients with plaque psoriasis when compared with the expression observed in adjacent non-lesional tissues. In vitro studies further demonstrated that in the presence of IL-29, HaCaT keratinocytes with IL28RA knockdown exhibited a faster rate of proliferation than control cells, and an enhanced ratio of cells in the S and G2/M phase. By contrast, IL28RA overexpression inhibited the proliferation of HaCaT keratinocytes and caused cell cycle arrest at the G0/G1 phases. Western blot analysis revealed that knockdown of IL28RA upregulated cyclinB1 expression and downregulated cyclinE expression; the opposite results were observed in the IL28RA-overexpressing HaCaT cells. Finally, a mechanistic study revealed that IL28RA functions through the activation of the Janus kinase-signal transducer and activator of transcription signaling pathway to exert its anti-proliferative effect. These results suggested that weak expression of IL28RA may contribute to the pathogenesis of psoriasis and that IL28RA may be an effective drug target for the treatment of psoriasis. However, further in vivo studies are required.

Possible association of proinflammatory cytokine IL-19 gene polymorphism with psoriasis

Background: Interleukin (IL-19) a member of the IL-10 family involved in abnormal keratinocyte differentiation and proliferation which is the hall mark of psoriasis. Aim: The aim of this study was to investigate the association between IL-19 gene polymorphism in patients with chronic plaque psoriasis as a factor in the susceptibility and development of psoriasis. Subjects and Methods: 200 psoriatic patients and 200 controls were genotyped for three IL-19 polymorphic sites by Amplification Refractory Mutation System polymerase chain reaction (ARMS-PCR). Results: Our results demonstrated that polymorphism of IL-19-42232 C/A (rs2243188) adjusted* OR=0.59; (95% CI=0.25 – 1.40)and IL-19-38386 T/C (rs2073186) adjusted* OR=1.28; (95% CI=0.70 – 2.35) does not show any significant association with risk of psoriasis while as IL-19 -35402 G/C (rs2243158) adjusted* OR=2.05; (95% CI=1.19 – 3.55) was found to be in association with increased risk of psoriasis. HT3 ACG OR=0.41; (95% CI=0.20- 0.84) haplotype is associated with decreased risk of psoriasis. Limitations: Small sample size. A large epidemiological study is required to confirm these findings. Family based studies and association studies of different populations are required to confirm the impact of IL-19 in genetic predisposition of psoriasis. Conclusion: IL-19 polymorphism have considerable role towards the susceptibility of psoriasis in north Indian population. Evaluating the role of IL-19 cytokine in pathogenesis of psoriasis will prove supportive for the development of psoriasis management.

Methylenetetrahydrofolate Reductase C677T Gene Polymorphism as Risk Factor for Psoriasis in Saudis.

Methylenetetrahydrofolate reductase (MTHFR) has been linked with the etiopathogenesis of psoriasis with inconsistent results. Methylenetetrahydrofolate reductase C677T polymorphism was evaluated in 106 Saudi psoriasis vulgaris patients and 280 matched healthy controls using PCR-RFLP (restriction fragment length plymorphism) technique. The cardiovascular risk factors were also compared in cases and controls. Allele T and genotypes CT and TT were found to be increased while allele C and genotype CC significantly decreased in psoriasis patients as compared with controls (P < .001). These results showed that the T-allele and T-containing genotypes (TT, CT) of MTHFR C677T are significantly linked with psoriasis susceptibility while C-allele and CC genotype are protective for it. Body mass index, fasting glucose, total cholesterol, low-density lipoprotein, triglycerides, and C-reactive protein, known markers for cardiovascular diseases, were found to be significantly elevated in the patient group as compared with the controls. It is concluded that the MTHFR C677T polymorphism increases psoriasis risk in Saudi patients.

Clinical Implication and the Hereditary Factors of NM23 in Hepatocellular Carcinoma Based on Bioinformatics Analysis and Genome–Wide Association Study

NM23 expression is closely associated with hepatocellular carcinoma (HCC) recurrence, but the hereditary factors influencing NM23 levels are unknown. Using public database, the diagnostic value of NM23 in HCC was investigated. A total of 424 hepatitis B virus- (HBV-) related HCC patients were enrolled to perform a genome–wide association study for identifying candidate variants associated with NM23 expression level. Additionally, a logistic regression model, haplotypes, and survival analysis were performed in the subsequent analysis. We identified high NM23 expression levels that have a diagnostic accuracy in HCC tissues and had a poor recurrence-free survival in HBV-related HCC patients. Variants near Psoriasis susceptibility 1 candidate 1 (PSORS1C1) and StAR related lipid transdomain containing 3 (STARD3) are associated with NM23 expression. The PSORS1C1 haplotype TGCACA and the STARD3 haplotype GG have favorable cumulative effects on NM23 expression. Further, variants in PSORS1C1 were associated with either overall survival (rs556285588, rs3095301, and rs3131003) only or overall survival and recurrence-free survival (rs560052000 and rs541820233) both in HCC patients. Our findings suggested that variants at the PSORS1C1 and STARD3 loci play an important role in NM23 regulation. Moreover, variants in PSORS1C1 are potential biomarkers for the prediction of postoperative clinical outcomes in HBV-related HCC patients. Thus, variants in PSORS1C1 and STARD3 are associated with NM23 expression and clinical outcomes of HBV-related HCC patients, which may be regarded as potential biomarkers for this disease.

Investigation of Psoriasis Susceptibility Loci in Psoriatic Arthritis and a Generalized Pustular Psoriasis Cohort.

Psoriasis is a common skin disease affecting 1-3% of the population (Gelfand etal., 2005; Ferrándiz etal., 2001). Approximately 30% of patients with psoriasis develop psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis (Haroon etal., 2013; Prey etal., 2010). Generalized pustular psoriasis (GPP) affects about 1.3% of psoriasis patients. Recently, numerous novel susceptibility loci for psoriasis vulgaris (PsV) have been discovered thorough the application of genome-wide association studies (GWASs). Among them, the major histocompability complex is the locus with the strongest effect. Outside the major histocompability complex region, the novel susceptibility loci of PsV can be incorporated into an integrated pathogenic model comprising distinct signaling networks affecting skin barrier function, innate immune responses involving NF-κB signaling, and adaptive immune responses involving CD8 T cells and IL-23/IL-17-mediated lymphocyte signaling. Compared with PsV, only three GWASs were performed in PsA (Ellinghaus etal., 2012; Hüffmeier etal., 2010; Stuart etal., 2015), accompanied with other candidate gene studies, most of the PsA susceptibility loci have been proved to be associated with PsV. However, the genetic study of GPP is quite different. Up to now, IL36RN is the only associated gene of GPP that has been widely verified. The data are based on homozygosity mapping and direct sequencing in consanguineous Tunisian multiplex families with autosomal recessive GPP (Marrakchi etal., 2011). Some researchers suggested that GPP and PsV are etiologically distinct clinical entities (Capon, 2013), challenging the traditional understanding of psoriasis. The percentages of IL36RN-negative patients have been reported to range from 51% (Li etal., 2013) to 84% (Setta-Kaffetzi etal., 2013), implying that additional risk loci, genetic interactions, and other factors may account for the other GPP cases. Recently, more than 10 GWASs of PsV have identified a number of susceptibility loci, making PsV GWASs a rich source of potential risk loci for other subtypes of psoriasis. Here, we use information emerging form PsV GWASs to make inferences about the genetic etiology of PsA and GPP in a Chinese population.

Vitamin D receptor ApaI, TaqI, BsmI, and FokI polymorphisms and psoriasis susceptibility: an updated meta-analysis.

Vitamin D is considered a regulator of the immune system, and its polymorphisms have been associated with psoriasis in some but not all reports. To explore whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to psoriasis. Meta-analyses were conducted to determine the associations between psoriasis and the VDR ApaI, TaqI, BsmI and FokI polymorphisms in all participants, and stratified by ethnic group. In total, 16 studies on VDR polymorphisms and psoriasis were included in this meta-analysis, which involved 2086 patients and 2182 controls. The meta-analysis indicated an association between psoriasis and the VDR TaqI TT genotype in Caucasian (OR = 1.29, 95% CI = 1.00-1.66, P < 0.05), but not in Asian (OR = 1.32, 95% CI = 0.89-1.96, P = 0.16) populations. However, no association was found between psoriasis and the VDR TaqI polymorphism using dominant, allele contrast or homozygous contrast models. No association was found between psoriasis and either the VDR ApaI, BsmI or FokI polymorphisms by meta-analyses of the allele contrast, recessive, or dominant models or homozygous contrast models in the overall, Caucasian or Asian populations. This meta-analysis showed that polymorphisms in VDR ApaI, BsmI and FokI are not associated with psoriasis susceptibility in overall, Caucasian or Asian populations. However, the VDR TaqI polymorphism is associated with psoriasis susceptibility in Caucasian populations.

Expanded Genome-Wide Association Study Meta-Analysis of Psoriasis Expands the Catalog of Common Psoriasis-Associated Variants.

Psoriasis is a complex immune-mediated disease of skin and joints with a prevalence of about 2%. Previous genetic association studies have identified more than 60 psoriasis susceptibility loci, 47 of which were identified in Caucasians. To further understand the genetic architecture of this disease, we conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts (seven GWAS and one Immunochip dataset), with a combined effective sample size of more than 39,000 individuals. Approximately half (n= 22) of the 47 European-origin loci were identified in cohorts containing a large proportion (≥50%) of samples genotyped using the Immunochip (Bowes etal., 2015; Stuart etal., 2015; Tsoi etal., 2012a, 2015), a platform that focuses on genetic variants from promising signals identified in previous association studies of autoimmune diseases (Stuart etal., 2015). However, restricting analysis to markers genotyped (∼110,000) (Tsoi etal., 2012b) or well-imputed (∼700,000) (Tsoi etal., 2015) on the Immunochip limits exploration of the full genome for susceptibility loci.

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.

Psoriasis Plays a Wild CARD

Rare autosomal mutations in CARD14 have previously been linked to psoriasis susceptibility in humans, but their pathogenic role had not been shown. Mellett etal. generated mice harboring the patient-derived gain-of-function Card14ΔE138 mutation and showed that hyperactivation of CARD14 alone is sufficient to induce immunopathogenic mechanisms that are responsible for psoriasis, which is driven by the IL-17/IL-23 axis.

Epigenome-wide DNA methylation regulates cardinal pathological features of psoriasis

BackgroundPsoriasis is a chronic inflammatory autoimmune skin disorder. Several studies suggested psoriasis to be a complex multifactorial disease, but the exact triggering factor is yet to be determined. Evidences suggest that in addition to genetic factors, epigenetic reprogramming is also involved in psoriasis development. Major histopathological features, like increased proliferation and abnormal differentiation of keratinocytes, and immune cell infiltrations are characteristic marks of psoriatic skin lesions. Following therapy, histopathological features as well as aberrant DNA methylation reversed to normal levels. To understand the role of DNA methylation in regulating these crucial histopathologic features, we investigated the genome-wide DNA methylation profile of psoriasis patients with different histopathological features.ResultsGenome-wide DNA methylation profiling of psoriatic and adjacent normal skin tissues identified several novel differentially methylated regions associated with psoriasis. Differentially methylated CpGs were significantly enriched in several psoriasis susceptibility (PSORS) regions and epigenetically regulated the expression of key pathogenic genes, even with low-CpG promoters. Top differentially methylated genes overlapped with PSORS regions including S100A9, SELENBP1, CARD14, KAZN and PTPN22 showed inverse correlation between methylation and gene expression. We identified differentially methylated genes associated with characteristic histopathological features in psoriasis. Psoriatic skin with Munro’s microabscess, a distinctive feature in psoriasis including parakeratosis and neutrophil accumulation at the stratum corneum, was enriched with differentially methylated genes involved in neutrophil chemotaxis. Rete peg elongation and focal hypergranulosis were also associated with epigenetically regulated genes, supporting the reversible nature of these characteristic features during remission and relapse of the lesions.ConclusionOur study, for the first time, indicated the possible involvement of DNA methylation in regulating the cardinal pathophysiological features in psoriasis. Common genes involved in regulation of these pathologies may be used to develop drugs for better clinical management of psoriasis.

Transforming growth factor-β1 gene polymorphism in psoriasis vulgaris.

BackgroundIncreased transforming growth factor beta 1 (TGF-β1) in the epidermis and serum has been found in psoriatic patients. The mechanism for this increase remains unclear.ObjectiveTo study the TGF-β1 gene polymorphism at codon 10 and its relation to psoriasis susceptibility in a sample of Egyptian patients.Materials and methodsThis cross-sectional study involved 70 patients with psoriasis vulgaris and 100 age- and sex- comparable healthy volunteers as a control group. Genomic DNA was prepared from peripheral blood lymphocytes from all subjects using QIAamp DNA mini kit (QIAGEN Inc., Germany). The TGF-β1 polymorphism was genotyped by PCR-based restricted fragment length polymorphism (PCR-RFLP) analysis. Amplification of codon 10, located in exon 1 of TGFβ1 gene was done through PCR reaction using gene-specific primers.ResultsStatistically significant difference was found between psoriasis patient and controls as regards TGF-β1 (T869C) polymorphism (P=0.045). The presence of TT genotype was associated with a 3-fold risk of psoriasis compared to CC genotype (P=0.016, OR: 3.13 95% CI: 1.24–7.88). T allele was significantly more frequent in psoriasis patients (P=0.017). TGF-β1 gene mutation was significantly higher among psoriasis patients with positive family history (P=0.007).ConclusionTGF-β1 gene polymorphism at codon 10 (T869C) is significantly associated with susceptibility to psoriasis in Egyptian patients. This polymorphism is more common in patients with a positive family history of psoriasis.

A safety evaluation of guselkumab for the treatment of psoriasis

ABSTRACTIntroduction: Guselkumab is a fully human monoclonal IgG1λ antibody for the treatment of plaque psoriasis that inhibits interleukin (IL)-23p19 subunit, reducing the proliferation of type 17 helper T (Th-17) cells and thus production of Th-17-derived pro-inflammatory cytokines, especially IL-17 and IL-22.Areas covered: In the following article, the mechanism of action and mainly the efficacy and safety profile of guselkumab available from results of trials will be discussed. We summarized these data after a literature review including PubMed search, relating proceedings and abstracts from relevant international conferences, assessment reports from European and United States regulatory agencies and treatment guidelines up to April 2018.Expert opinion: The central role of IL-23 in psoriasis pathogenesis is supported by genetic links of IL-23 and IL-23R alleles to psoriasis susceptibility; early clinical trials have demonstrated that sufficient inhibition of IL-23p19 results in rapid resolution of the disease. Targeting IL-23, may be responsible for the high efficacy and durable responses of guselkumab, avoiding some adverse effects of IL-17A blockade, like mucocutaneous candida infections or triggering/worsening of inflammatory bowel disease, experienced with agents acting selectively against this molecule and that seem to be class related.

Periostin (rs3829365) Gene Polymorphism and Cardiac Function in Psoriasis

Psoriasis considered a chronic inflammatory skin disease characterized by spontaneous remissions and exacerbations. The lesions are characterized by circumscribed, dry, erythematous plaques of various sizes covered by silvery white scales. Periostin gene (POSTN) in human is located in the long arm of chromosome 13 (13q13.3) and spans approximately 36 kb, It has 23 exons and encodes for a protein of 836 amino acids with a molecular weight of 93 kD, it was renamed periostin due to itˈs localized expression in the periosteum and the periodontal ligament.The aim of this study was to reveal the association between periostin (rs3829365) gene polymorphism and psoriasis susceptibility. Blood samples were taken from psoriasis patients and control group for genotyping of Periostin gene using PCR. Regarding periostin gene polymorphism, CG and GG genotypes showed higher distributions among psoriasis patients than control and total polymorphism showed higher distributions when compared to CC genotype frequency and G allele carry a risk factor for psoriasis susceptibility.Periostin genpolymorphism(rs3829365) genotypes frequencies CG,GG and(CG+GG) and G allele might play a role in psoriasis pathogenesis.

The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells

Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO+ (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.

The polymorphisms of growth factor genes (VEGFA & EGF) were associated with response to acitretin in psoriasis.

VEGF and EGF are assumed to be involved in the pathogenesis of psoriasis, while the impacts of their polymorphisms on psoriasis are inconsistent. Therefore, we hope to clarify these relationships in the Chinese Han population. A total of 131 patients with psoriasis vulgaris and 176 controls were enrolled. The polymorphisms rs833061 (T>C), rs10434 (G>A) in VEGFA, and rs4444903 (G>A), rs2237051 (A>G) in EGF of each participant were detected. The patients were treated with calcipotriol plus acitretin 30mg/day for 8weeks. No SNPs of rs833061, rs10434, rs4444903 and rs2237051 were found to be associated with psoriasis susceptibility and efficacy. Although the mutation of rs10434A was associated with baseline disease severity (p =0.026), and rs2237051G allele was associated with increased erythema during treatment (p =0.015). The allele of rs2237051 G increased the erythema during the treatment, and no polymorphism of VEGF and EGF gene was found to be associated with the susceptibility and efficacy in psoriasis.

A catalog of potential putative functional variants in psoriasis genome-wide association regions.

Psoriasis is a common inflammatory skin disease, with considerable genetic contribution. Genome-wide association studies have successfully identified a number of genomic regions for the risk of psoriasis. However, it is challenging to pinpoint the functional causal variants and then further decipher the genetic mechanisms underlying each region. In order to prioritize potential functional causal variants within psoriasis susceptibility regions, we integrated the genetic association findings and functional genomic data publicly available, i.e. histone modifications in relevant immune cells. We characterized a pervasive enrichment pattern of psoriasis variants in five core histone marks across immune cells/tissues. We discovered that genetic alleles within psoriasis association regions might influence gene expression levels through significantly affecting the binding affinities of 17 transcription factors. We established a catalog of 654 potential functional causal variants for psoriasis and suggested that they significantly overlapped with causal variants for autoimmune diseases. We identified potential causal variant rs79824801 overlay with the peaks of five histone marks in primary CD4+ T cells. Its alternative allele affected the binding affinity of transcription factor IKZF1. This study highlights the complex genetic architecture and complicated mechanisms for psoriasis. The findings will inform the functional experiment design for psoriasis.