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Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. Key Points: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree [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 A(H7N9) virus strain that emerged in 2013 was associated with a high fatality rate and may become a long-term threat to public health. A(H7N9) disease incidence is disproportionate to viral exposure, suggesting that host genetic factors may significantly influence susceptibility to A(H7N9) infection. Human genome variation in conferring risk for A(H7N9) infection in Chinese populations was identified by a two-stage investigation involving 121 A(H7N9) patients and 187 healthy controls using next generation sequencing followed by functional analysis. As a result, a low frequency variant (rs189256251; P = 0.0303, OR = 3.45, 95% CI 1.05–11.35, chi-square test) and three HLA alleles (DQB1*06:01, DQA1*05:05 and C*12:02) were identified in A(H7N9) infected volunteers. In an A549 cell line carrying the rs189256251 variant CT genotype, A(H7N9) infection incidence was elevated 6.665-fold over control cells carrying the CC genotype. Serum levels of interferon alpha were significantly lower in patients with the CT genotype compared to the CC genotype (P = 0.01). The study findings of genetic predisposition to A(H7N9) in the Chinese population may be valuable in systematic investigations of A(H7N9) disease etiology. [ABSTRACT FROM AUTHOR]

To verify whether PsA-associated HLA alleles proposed in other populations are also related to PsA in Chinese Han population, a study of PsA susceptible alleles in the HLA-A, HLA-B, HLA-C and HLA-DRB1 alleles was presented for Chinese Han population. Genotyping was performed by Illumina Miseq platform (Illumina, USA). 50 subtypes and 77 subtypes of HLA-A, HLA-B, HLA-C and HLA-DRB1 with minor allele frequency (MAF) > 1% were genotyped from two-digit and four-digit resolution analysis in 111 PsA and 207 HCs (healthy controls) collected from Chinese Han population, respectively. Data handling, quality control and association analysis were performed using SPSS 25.0 software. In risk estimate, by mean of Bonferroni correction, a newfound four-digit allele HLA-A*01:01 [P = 5.5 × 10−4, OR 3.35 (1.69–6.66)], four-digit allele HLA-C*06:02 [P = 8.5 × 10−7, OR 3.80 (2.23–6.47)] and six two-digit alleles HLA-A*01 [P = 5.2 × 10−5, OR 3.43 (1.89–6.23)], HLA-B*13 [P = 4.0 × 10−6, OR 2.65 (1.76–4.01)], HLA-B*27 [P = 7.5 × 10−4, OR 5.84 (2.09–16.29)], HLA-B*57 [P = 5.8 × 10−5, OR 20.10 (4.65–86.83)], HLA-C*03 [P = 2.1 × 10−4, OR 0.40 (0.25–0.65)], HLA-C*06 [P = 1.9 × 10−12, OR 4.48 (2.95–6.81)] showed statistical significance by the univariate binary logistic regression analysis. Besides, in the binary logistic regression analysis with multiple variables, when the two alleles HLA-A*01:01 and HLA-C*06:02 were considered as covariates, HLA-A*01:01 [P = 2.7 × 10−3,OR 2.95 (1.46–5.98)] also showed significant association for PsA as risk factor, but may be not the main risk factor [HLA-C*06:02, P = 3.0 × 10−6, OR 3.68 (2.13–6.37)]. When all the above two-digit alleles were included as covariates, HLA-A*01 [P = 4.8 × 10−2, OR 2.00 (1.01–3.94)], HLA-B*13 [P = 4.2 × 10−5, OR 2.62 (1.65–4.16)], HLA-B*27 [P = 1.7 × 10−4, OR 7.62 (2.64–21.96)], HLA-B*57 [P = 2.97 × 10−4, OR 15.90 (3.55–71.18)], HLA-C*06 [P = 6.1 × 10−5, OR 2.70 (1.66–4.40)] showed significant for PsA as risk factors, HLA-C*03 [OR 0.65 (0.39–1.09), P = 0.10] showed no association with PsA. In conclusion, we assessed HLA-A, HLA-B, HLA-C and HLA-DRB1 alleles in PsA cohort of Chinese Han population, found HLA-A*01:01 and HLA-A*01 may be the susceptible genes associated with PsA, and also confirmed the association of four loci with PsA in Chinese Han population. These findings may extend the susceptibility HLA alleles of PsA and help in developing possible genetic markers to predict PsA. [ABSTRACT FROM AUTHOR]

Psoriasis (Ps) is an inflammatory skin disease caused by genetic and environmental factors. Previous studies on DNA methylation (DNAm) found genetic markers that are closely associated with Ps, and evidence has shown that DNAm mediates genetic risk in Ps. In this study, Consensus Clustering was used to analyze DNAm data, and 114 Ps patients were divided into three subclassifications. Investigation of the clinical characteristics and copy number variations (CNVs) of DEFB4, IL22, and LCE3C in the three subclassifications revealed no significant differences in gender ratio and in Ps area and severity index (PASI) score. The proportion of late-onset ( ≥ 40 years) Ps patients was significantly higher in type I than in types II and III (P = 0.035). Type III contained the smallest proportion of smokers and the largest proportion of non-smoking Ps patients (P = 0.086). The CNVs of DEFB4 and LCE3C showed no significant differences but the CNV of IL22 significantly differed among the three subclassifications (P = 0.044). This study is the first to profile Ps subclassifications based on DNAm data in the Chinese Han population. These results are useful in the treatment and management of Ps from the molecular and genetic perspectives. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a chronic inflammatory skin disease and is affected by environmental and genetic factors. Gene-gene/environment interactions are strongly believed to contribute to the genetic risk of common diseases. A number of gene-environment interactions of atopic dermatitis were performed. However, there are few comprehensive investigations on the gene-gene (or genetic variants) interactions for atopic dermatitis. We explored the association model of 6 single nucleotide polymorphisms (SNPs) which were most significant ( P < 10E-05) in our previous genome wide association study (GWAS) for atopic dermatitis, and search for the possible genetic variant interactions based on the previous GWAS data using Generalized Multifactor Dimensionality Reduction and Plink 1.07 in the combined sample of 4,636 cases and 13,559 controls. The most significant associated evidence was observed under dominant model for SNPs rs3126085, rs12085366, and rs7701890, recessive model for SNP rs17173197, and additive model for SNPs rs2393903 and rs6010620. Three significant pair-way interactions were observed, including PRKAG2 and FLG SNPs (rs17173197 × rs3126085, P = 1.11E-15), PRKAG2 and TMEM232- SLC25A46 SNPs (rs17173197 × rs7701890, P = 2.22E-15), PRKAG2 and TNFRSF6B- ZGPAT SNPs (rs17173197 × rs6010620, P = 6.66E-16). Besides, a three-way significant interaction among PRKAG2, TMEM232- SLC25A46 and TNFRSF6B- ZGPAT SNPs (rs17173197 × rs7701890 × rs6010620, P = 5.99E-15) was observed in this study. These four genetic variant interactions confer susceptibility to atopic dermatitis, and highlight the genetic variant interactions in the etiology of atopic dermatitis in Chinese Han population. [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]

This corrects the article DOI: 10.1038/ncomms7793 [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with high heritability, although the underlying genetic determinants of ASDs remain largely unknown. Large-scale whole-genome studies of copy number variation in Han Chinese samples are still lacking. We performed a genome-wide copy number variation analysis of 343 ASD trios, 203 patients with sporadic cases and 988 controls in a Chinese population using Illumina genotyping platforms to identify CNVs and related genes that may contribute to ASD risk. We identified 32 rare CNVs larger than 1 Mb in 31 patients. ASD patients were found to carry a higher global burden of rare, large CNVs than controls. Recurrent de novo or case-private CNVs were found at 15q11-13, Xp22.3, 15q13.1-13.2, 3p26.3 and 2p12. The de novo 15q11-13 duplication was more prevalent in this Chinese population than in those with European ancestry. Several genes, including GRAMD2 and STAM, were implicated as novel ASD risk genes when integrating whole-genome CNVs and whole-exome sequencing data. We also identified several CNVs that include known ASD genes (SHANK3, CDH10, CSMD1) or genes involved in nervous system development (NYAP2, ST6GAL2, GRM6). Besides, our study also implicated Contactins-NYAPs-WAVE1 pathway in ASD pathogenesis. Our findings identify ASD-related CNVs in a Chinese population and implicate novel ASD risk genes and related pathway for further study. [ABSTRACT FROM AUTHOR]