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Background: Psoriasis is a chronic and hyperproliferative skin disease featured by hyperkeratosis with parakeratosis, Munro micro-abscess, elongation of rete pegs, granulosa thinning, and lymphocyte infiltration. We previously profiled gene expression and chromatin accessibility of psoriatic skins by transcriptome sequencing and ATAC-seq. However, integrating both of these datasets to unravel gene expression regulation is lacking. Here, we integrated transcriptome and ATAC-seq of the same psoriatic and normal skin tissues, trying to leverage the potential role of chromatin accessibility and their function in histopathology features. Results: By inducing binding and expression target analysis (BETA) algorithms, we explored the target prediction of transcription factors binding in 15 psoriatic and 19 control skins. BETA identified 408 upregulated genes (rank product < 0.01) and 133 downregulated genes linked with chromatin accessibility. We noticed that cumulative fraction of genes in upregulation group was statistically higher than background, while that of genes in downregulation group was not significant. KEGG pathway analysis showed that the upregulated 408 genes were enriched in TNF, NOD, and IL-17 signaling pathways. In addition, the motif module in BETA suggested the 57 upregulated genes are targeted by transcription factor AP-1, indicating that increased chromatin accessibility facilitated the binding of AP-1 to the target regions and further induced expression of relevant genes. Among these genes, SQLE, STRN, EIF4, and MYO1B expression was increased in patients with hyperkeratosis, parakeratosis, and acanthosis thickening. Conclusions: In summary, with the advantage of BETA, we identified a series of genes that contribute to the disease pathogenesis, especially in modulating histopathology features, providing us with new clues in treating psoriasis. [ABSTRACT FROM AUTHOR]

Background: Vitiligo is a complex disease in which patchy depigmentation is the result of an autoimmune-induced loss of melanocytes in affected regions. On the basis of a genome-wide linkage analysis of vitiligo in the Chinese Han population, we previously showed significant evidence of a linkage between 22q12 and vitiligo. Our aim in the current study was to identify vitiligo susceptibility variants within an expanded region of the 22q12 locus. Methods and results: An in-depth analysis of the expanded region of the 22q12 locus was performed by imputation using a large GWAS dataset consisting of 1117 cases and 1701 controls. Eight nominal SNPs were selected and genotyped in an independent cohort of Chinese Han individuals (2069 patients and 1370 control individuals) by using the Sequenom MassArray iPLEX1 system. The data were analyzed with PLINK 1.07 software. The C allele of rs730669 located in ZDHHC8/RTN4R showed a strong association with vitiligo (P = 3.25 × 10–8, OR = 0.81). The C allele of rs4820338 located in VPREB1 and the A allele of rs2051582 (a SNP reported in our previous study) located in IL2RB showed a suggestive association with vitiligo (P = 1.04 × 10–5, OR = 0.86; P = 1.78 × 10–6, OR = 1.27). The three identified SNPs showed independent associations with vitiligo in a conditional logistic regression analysis (all P < 1.0 × 10–5; all D′ < 0.05 and r2 < 1.0 × 10–4). Conclusions: The study reveals that two novel variants rs730669 (ZDHHC8/RTN4R) and rs4820338 (VPREB1) on 22q11.2 might confer susceptibility to vitiligo and affect disease subphenotypes. The presence of multiple independent variants emphasizes their important roles in the genetic pathogenesis of disease. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal activation of T cells and caused by an imbalance in the production and clearance of apoptotic cells. We previously showed that the transcription regulator Bach2 regulated abnormal B‐cell activation in SLE. Here, we investigated whether Bach2 was also involved in Th9 cell differentiation in SLE. We found that the proportion of Th9 cells was enhanced in the peripheral blood mononuclear cells (PBMC) of SLE patients. The PBMC and CD4+ T cells of SLE patients exhibited a decrease of Bach2 expression and an increase of IL‐9 expression. Furthermore, Bach2 overexpression significantly repressed the levels of PU.1, IRF4, IL‐9, and Th9 cells in the CD4+ T cells of SLE patients and healthy volunteers. In addition, Bach2 overexpression inhibited the levels of IL‐9 and Th9 cells, whereas IRF4 upregulation enhanced the levels of IRF4 and IL‐9 and Th9 cells in the CD4+ T cells of SLE patients and healthy volunteers. The effect of IRF4 up‐regulation was abolished by Bach2 overexpression. In summary, our work suggests that Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in SLE, and thus, Bach2 may be a novel potential target for SLE treatment. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease which mainly involves immune system. This research was to investigate the role of MST1 in the psoriasis, and the detailed mechanism whether related with Th17 and NF-κB. The skin samples and peripheral blood were obtained from psoriasis patients. Skin samples and T cells isolated from peripheral blood of patients were cultured in vitro. The results showed that the level of MST1 in the lesional skin of all three patients was higher than that of un-lesional skin, as well as the amount of CD4, CD8 and IL17 positive T cells. The amount of circulating Th17 was higher than that of control. The level of MST1, IL-17, IL-22 and TNFα was enhanced in activated T cells (p < 0.01), which indicated that MST1 increased markedly in activated T cells. The proliferation and migration of T cells were decreasing in MST1 knockdown cells, while increasing in overexpressed cells, as well as the production of IL-17, IL-22 and TNFα. MST1 enhanced the activation of TLR4-NF-κB signaling pathway, and TLR4 knockdown could reverse the effect of MST1 on NF-κB activation. This research indicated that MST1 could regulate the activation of Th17 in psoriasis partly through TLR4-NF-κB pathway. MST1 may be a target for treatment of psoriasis. [ABSTRACT FROM AUTHOR]

The skin microbiota is an inseparable component of the skin barrier structure, which participates in the stabilization or impairment of the barrier function as well as the development of many skin diseases. To characterize the normal skin microbiota and its association with skin sites, age and sex, we recruited 50 volunteers divided into children, adolescents, young adults, middle‐aged adults and the elderly. The skin sites consisted of cheeks, volar forearms (representing dry environments) and upper back (representing sebaceous environments). A total of 9 574 365 high‐quality sequences of the V3 to V4 region of the 16S rRNA gene were annotated with taxonomic information related to two archaeal phyla (Thaumarchaeota and Euryarchaeota) and five dominant bacterial phyla (Actinobacteria, Proteobacteria, Firmicutes, Bacteroidetes and Cyanobacteria). The skin bacteria community structure was influenced by skin sites, and was closely related to age and sex. The upper back was dominated by Propionibacterium and Staphylococcus, and the cheeks facilitated the survival of Betaproteobacteria, while Alphaproteobacteria were prevalent on the volar forearms. Regarding the effects of age, after sexual maturity, the cheek microbiota became more similar to sebaceous sites (i.e. the upper back). The volar forearms appeared to experience the aging process earlier than the other two sites. The elderly had greater species richness and diversity and their community composition no longer had skin‐site selectivity. Males had a greater species richness than females, but the sex differences in the community structure only present at certain age groups and skin sites. [ABSTRACT FROM AUTHOR]

Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other immune-related diseases. However, there is no reported study on the associations between immune susceptibility polymorphisms and the risk of vitiligo with immune-related diseases. The aim of this study was to evaluate the potential influence of 10 single-nucleotide polymorphisms (SNPs) at 18q21.31 (rs10503019), 4p16.1 (rs11940117), 3q28 (rs1464510), 14q12 (rs2273844), 12q13.2 (rs2456973), 16q12.2 (rs3213758), 10q25.3 (rs4353229), 3q13.33 (rs59374417), and 10p15.1 (rs706779 and rs7090530) on vitiligo with immune-related diseases in the Chinese Han population. All SNPs were genotyped in 552 patients with vitiligo-associated immune-related diseases and 1656 controls using the Sequenom MassArray system. Data were analyzed with PLINK 1.07 software. The C allele of rs2456973 at 12q13.2 was observed to be significantly associated with vitiligo-associated immune-related diseases (autoimmune diseases and allergic diseases) ( P = 0.0028, odds ratio (OR) = 1.27). In subphenotype analysis, the rs2456973 C allele was also significantly associated with early-onset vitiligo by comparing with controls ( P = 0.0001) and in the case-only analysis (P = 0.0114). We confirmed that 12q13.2 was an important candidate locus for vitiligo with immune-related diseases (autoimmune diseases and allergic diseases) and affected disease phenotypes with early onset. [ABSTRACT FROM AUTHOR]

Background: We confirmed that the filaggrin gene mutation c.3321delA is associated with atopic dermatitis in our previous genome wide association study of the Chinese Han population. c.3321delA is the most common filaggrin gene mutation in Chinese atopic dermatitis patients but is not present in European populations. Objective: To investigate the genetic model for the c.3321delA mutation and to determine the correlation between c.3321delA and atopic dermatitis clinical phenotypes in the Chinese Han population. Method: The filaggrin gene mutation c.3321delA was sequenced in 1,080 atopic dermatitis patients and 908 controls from the Chinese population. The χ2 test, ANOVA,nonparametric tests and logistic regression were used to investigate the relationship between the c.3321delA genotype and atopic dermatitis clinical phenotypes in the Chinese Han population. Results: Analyses of the genetic model revealed that the additive model best described the c.3321delA mutation (P = 3.09E-11, OR = 3.43, 95%CI = 2.38–4.96). Stratified analyses showed that the c.3321delA allele frequency distribution is significantly associated with concomitant skin xerosis (P = 1.68E-03, OR = 2.13,95%CI = 1.32–3.46), palmar hyperlinearity (P = 3.64E-17, OR = 4.0,95%CI = 2.86–5.70), white dermatographism (P = 4.25E-03, OR = 1.82,95%CI = 1.22–2.71), food intolerance (P = 1.51E-03, OR = 1.76,95%CI = 1.23–2.50) and disease severity ( P = 9.67E-05). Conclusion: Our study indicates that the filaggrin gene mutation c.3321delA is associated with clinical phenotypes of atopic dermatitis in the Chinese Han population, which might help us gain a better understanding on the pathogenesis of atopic dermatitis. [ABSTRACT FROM AUTHOR]

Psoriasis is a common immune-mediated inflammatory skin disease with strong genetic components, in which the IL23/Th17 pathway has been implicated. To explore the effective role in psoriasis, we genotyped five single nucleotide polymorphisms in genes related to IL23/Th17 pathway in 14,929 Han Chinese samples. A Bonferroni-corrected significant single-variant association was identified between rs1512970 within IL21 (odds ratio (OR) = 1.07, 95 % confidence interval (CI) = 1.02-1.13, P = 4.94 × 10). We failed to validate rs744166 (OR = 1.06, 95 % CI = 1.01-1.11, P = 1.52 × 10) and other three SNPs ( P = 2.48 × 10 ∼ 1.27 × 10) to meet the single-variant association significance threshold. However, we found that their combined effect substantially contributed to the risk of psoriasis in our sample ( P = 3.91 × 10) and the highest score group conferred the largest risk effect size (OR = 1.22, 95 % CI = 1.11-1.34, P = 1.85 × 10). Our results implicate the ethnic heterogeneity in the susceptibility of psoriasis and suggest common variants with weak effect in IL23/Th17 pathway, which do not show significance in conventional single-variant association study, may contribute to the risk of psoriasis. This study sheds light on the important role of IL23/Th17 pathway in the susceptibility of psoriasis. [ABSTRACT FROM AUTHOR]

To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis. [ABSTRACT FROM AUTHOR]

Background: Androgenetic alopecia (AGA) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with AGA in the Chinese Han population. Methods: We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 AGA cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and AGA in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ≤3.13×10−3. Results: We identified that 5 SNPs at 20p11 were significantly associated with AGA in the Chinese Han population (1.84×10−11≤P≤2.10×10−6). Conclusions: This study validated, for the first time, that 20p11 also confers risk for AGA in the Chinese Han population and implicated the potential common genetic factors for AGA shared by both Chinese and European populations. [ABSTRACT FROM AUTHOR]

Psoriasis and psoriatic arthritis (PsA) is a complex autoimmune disease. NOD2/CARD15 gene has been suggested to play an important role in the pathogenesis of psoriasis and PsA. This study aims to assess the association between NOD2/CARD15 polymorphisms and the susceptibility to psoriasis/PsA. A meta-analysis was performed to survey studies on the NOD2/CARD15 polymorphisms and psoriasis/PsA using comprehensive PubMed, Embase, and Web of Science citation search. A total of 9 published studies were involved. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on fixed effects models or random effects models were depended on Cochran's Q-statistic. Potential publication bias was evaluated by Egger's linear regression test. As for R702W, the pooled ORs were 1.041 (95% CI 0.854-1.268, P = 0.693; 2,081 patients vs. 2,717 controls) for C allele and 0.886 (95% CI 0.565-1.391. P = 0.600; 1,222 patients vs. 1,818 controls) for genotype. Then for G908R, the pooled ORs were 1.042 (95% CI, 0.761-1.426, P = 0.799; 2,053 patients vs. 2,743 controls) for C allele and 0.942 (95% CI 0.708-1.254, P = 0.683; 1,226 patients vs. 1,824 controls) for the homozygous wild type. Then for Leu1007fsinsC allele polymorphism and genotype, the pooled ORs were 1.160 (95% CI, 0.893-1.507, P = 0.266; 2,279 patients vs. 3,067 controls) and 1.266 (95% CI 0.897-1.789, P = 0.180; 1,979 patients vs. 1,607 controls), respectively. No obvious publication bias was shown in the results. The association between NOD2/CARD15 polymorphisms and psoriasis/PsA was not found. Taken together, our results suggest that NOD2/CARD15 might not be a susceptibility gene for psoriasis and psoriatic arthritis. [ABSTRACT FROM AUTHOR]