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Freckle is a prevalent pigmentary dermatosis with an obvious hereditary component. Dozens of freckles risk loci have been discovered through research on multiple traits or other diseases, rather than as an independent trait. To discover novel variants associated with freckles, we performed GWAS and meta‐analysis in 4813 Chinese individuals. We conducted GWAS and meta‐analysis of two cohorts: 197 patients and 1603 controls (Cohort I), and 336 patients and 2677 controls (Cohort II), both from China. Then we performed linkage disequilibrium (LD) analysis, eQTL study, and enrichment analysis with association results for functional implications. Finally, we discovered 59 new SNPs and 13 novel susceptibility genes associated with freckles (Pmeta <5 × 10−8), which has enriched the genetic research on freckles. [ABSTRACT FROM AUTHOR]

Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin‐dependent protein kinase II‐γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g‐deficient mice exhibits attenuated imiquimod‐induced psoriasis‐like manifestations and skin inflammation. CaMK2γ regulates dermal γδT‐cell interleukin‐17 production in imiquimod‐treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor β1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve–norepinephrine–γδT cell–adrenoceptor β1–nuclear factor‐κB and –p38 axis activation. Application of alcaftadine, a small‐molecule CaMK2γ inhibitor, relieves imiquimod‐induced psoriasis‐like manifestations in mice. This study reveals the mechanisms of sympathetic‐nervous‐system regulation of γδT‐cell interleukin‐17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Acute urticaria is a prevalent inflammatory dermatosis characterized by fulminant wheals, often accompanied by severe pruritis. It may also cause nausea, vomiting, and abdominal pain. Numerous studies have substantiated the pivotal involvement of double‐stranded DNA (dsDNA) in autoimmunity. However, the role of dsDNA in the pathogenesis of acute urticaria is unclear.We measured serum dsDNA levels in patients and controls. The relationship between dsDNA levels and environmental exposures (temperature, ultraviolet [UV] index, and season) was investigated by correlating disease onset dates with archived meteorological data. Finally, we used quantitative PCR to determine the expressions of genes encoding dsDNA receptors, single‐stranded RNA (ssRNA) receptors, exosome formation, and type I interferon in the peripheral blood of patients and controls.Serum dsDNA levels were significantly higher in patients with acute urticaria compared with controls (mean values 1.38 and 0.94 ng/ml, respectively, P < 0.001). dsDNA levels were higher in patients exposed to higher environmental temperatures and UV indices and were higher during the summer months. We also found that the expressions of genes encoding dsDNA receptors, ssRNA receptors, absent in melanoma factor 2 (AIM2)‐related inflammatory factors, and interferon alpha were up‐regulated in patients.We demonstrated that serum dsDNA levels are elevated in acute urticaria and are influenced by climatic factors such as temperature, ultraviolet index, and season. We also found that elevated dsDNA promotes the expression of AIM2‐related factors and type I interferons. This study generates new hypotheses regarding the pathogenesis of acute urticaria and suggests novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial birth malformations in humans and are generally classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Genome‐wide association studies (GWASs) of NSOFCs have demonstrated multiple risk loci and candidate genes; however, published risk factors are able to explain only a small fraction of the observed NSOFCs heritability. Methods: Here, we performed GWASs of 1615 NSCPO cases and 2340 controls, and then conducted genome‐wide meta‐analyses of NSOFCs, totaling 6812 NSCL/P cases, 2614 NSCPO cases, and 19,165 controls from the Chinese Han population. Results: We identify 47 risk loci with genome‐wide pmeta‐value <5.0 × 10−8, 5 risk loci (1p32.1, 3p14.1, 3p14.3, 3p21.31, and 13q22.1) of which are new. All of the 47 susceptibility loci conjointly account for 44.12% of the NSOFCs' heritability in the Chinese Han population. Conclusion: Our results improve the comprehending of genetic susceptibility to NSOFCs and provide new views into the genetic etiology of craniofacial anomalies. [ABSTRACT FROM AUTHOR]

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]

In an article published in Advanced Science, researchers Qi Zhen, Liangdan Sun, and their colleagues discuss the role of sympathetic nerves in the development of psoriasis. They explain how the activation of CaMK2γ+ sympathetic nerves leads to increased production of interleukin-17 by dermal γδT cells, resulting in excessive inflammation associated with psoriasis. This study provides new insights into the mechanisms underlying the pathogenesis of psoriasis and highlights the potential for targeting sympathetic nerves as a therapeutic approach. [Extracted from the article]

Background/aims: Psoriasis is a chronic immune‐mediated inflammatory skin disease characterized by excessive proliferation of keratinocytes. It has a strong genetic predisposition; gene‐gene interactions are important genetic models for common diseases. In this study, we explore pair‐wise interactions among SNPs contributing to psoriasis susceptibility. Methods: We first performed gene interactions with exome‐sequencing, next, we analyzed gene interactions combining the exome sequencing data with the targeted sequencing data. After we sequenced HLA region, we analyzed gene interactions including HLA regions and non‐HLA regions. Results: We found interactions between HLA regions were significant. We observed significant interactions between HLA‐C*06:02 and rs118179173 (snp31443520; p = 8.21 × 10−20, OR = 0.22) and between HLA‐C*06:02 and HLA‐B:AA67 (p = 1.22 × 10−12, OR = 0.45). Conclusion: This study provides evidence that HLA is the most important susceptibility region on the risk of psoriasis and interactions that occur in this region are still significant. [ABSTRACT FROM AUTHOR]

• The level of AURKA increased in the psoriasis skin. • AURKA regulated the inflammatory responses of keratinocytes. • AURKA regulated autophagy in keratinocytes. • AURKA promoted the activation of the AKT/mTOR pathway. • AURKA regulated autophagy and inflammation through the AKT/mTOR pathway. • AURKA regulates AIM2 degradation through autophagy. Psoriasis is an immune-mediated genetic disease involving innate and the adaptive immune system. Aurora kinase A (AURKA) belongs to a seine/threonine kinases family and is elevated in lesional psoriatic tissues. This research aimed to investigate the effects of AURKA on psoriasis progression and whether it worked by regulating autophagy or inflammasome activation. The results showed that the expression of AURKA was higher in psoriasis tissue than that in the psoriasis skin. IFN- γ (100 ng/mL) plus poly (dA:dT) (2 mg/mL) induced the increased AURKA, secretion of IL-1 β , IL-18 and the active form of caspase-1 (p20). AURKA knockdown inhibited the inflammatory responses of keratinocytes and the activation of AIM2 inflammasome, and enhanced autophagy. 3MA (autophagy inhibitor) attenuated the effects of AURKA on AIM2 inflammasome. In addition, AURKA promoted the activation of the AKT/mTOR pathway. Akt inhibitor (PI-103) attenuated AIM2 inflammasome activation induced by Aurka overexpression. In conclusion, this research demonstrated that AURKA promoted the psoriasis-related inflammation by blocking autophagy-mediated AIM2 inflammasome suppression. AURKA has the potential to be explored as a new promising target for the treatment for psoriasis. [ABSTRACT FROM AUTHOR]

Background: Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods: Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results: A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion: Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene. [ABSTRACT FROM AUTHOR]

Background: Porokeratosis (PK) is a rare, heterogeneous group of keratinization disorders with an autosomal dominant inheritance pattern and is characterized by the presence of cornoid lamella. Disseminated superficial actinic PK is the most encountered subtype and typically manifests as multiple, small annular plaques with atrophic centers and slightly raised hyperkeratotic edges. Seven associated mutations (SSH1, SART3, MVKP, MVK, MVD, FDPS, and SLC17A9) have been reported in disseminated superficial actinic PK patients. Aim: We searched a Chinese disseminated superficial porokeratosis (DSAP) family to detect the causative genes. In the meantime, we reviewed the articles reported about DSAP in Chinese population, summarizing their clinical manifestations and discussing the incidence of DSAP in Chinese population. Materials and Methods: Sanger sequencing on the MVD and MVK genes was performed to identify the pathogenic mutation in a Chinese family with DSAP. Literature for DSAP cases reported in Chinese populations was searched by Sinomed and PubMed. Results: We identified the c. 875A > G (p. Asn292Ser) mutation in the MVD gene in the family. Conclusions: That mutation was a hotspot mutation. Literature review showed that the age of onset in DSAP family was earlier than that in sporadic patients; the lesion is common in the face in Chinese population which is distinct from studies in Caucasians; ultraviolet exposure is the main aggravating factor. [ABSTRACT FROM AUTHOR]

• Psychological stress aggravates imiquimod-induced psoriasiform inflammation in mice. • Stress-induced CORT elevation correlates with skin immune system alterations. • The CORT/GR signaling upregulates STAT1 phosphorylation to promote M1 macrophage polarization. • Blocking the CORT/GR signaling alleviates psoriasiform inflammation under stress. Psychological stress has long been considered to cause the aggravation and recurrence of psoriasis, but the underlying mechanism remains largely unknown. Here, we used a mouse model of restraint-induced stress and imiquimod (IMQ)-induced psoriasiform inflammation to investigate the crosstalk between stress and the skin immune system and their functions in the pathogenesis of psoriasis. We found that stress aggravated skin inflammation and elevated serum corticosterone (CORT) levels in mice. Stress also increased the number of macrophages and glucocorticoid receptor (GR) expression in IMQ-treated mouse skin. GR agonist CORT upregulated the phosphorylation of STAT1 to promote M1 macrophage polarization in vitro. Additionally, GR deletion in macrophages and pharmacologic inhibition of GR improved skin inflammation and reduced M1 macrophage polarization under stress. Taken together, these results indicate that stress aggravates psoriasiform inflammation by promoting CORT/GR signaling-induced M1 macrophage polarization, suggesting that blocking the GR signaling has great potential as an adjuvant treatment for psoriasis patients with chronic stress. [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]

Objective: Genome‐wide association studies have identified many susceptibility loci for systemic lupus erythematosus (SLE). However, most of these loci are located in noncoding regions of the genome. Long noncoding RNAs (lncRNAs) are pervasively expressed and have been reported to be involved in various diseases. This study aimed to explore the genetic significance of lncRNAs in SLE. Methods: A genome‐wide survey of SLE risk variants in lncRNA gene loci was performed in Han Chinese subjects (4,556 with SLE and 9,451 healthy controls). The functional relevance of an SLE risk variant in one of the lncRNA genes was explored using biochemical and molecular cell biology analyses. In vitro loss‐of‐function and gain‐of‐function strategies were used to clarify the functional and phenotypic relevance of this SLE susceptibility lncRNA. Moreover, correlation of this lncRNA with the degree of apoptosis in the peripheral blood of SLE patients was evaluated. Results: A novel SLE susceptibility locus in a lncRNA gene, designated SLEAR (for SLE‐associated RNA), was identified at the single‐nucleotide polymorphism rs13259960 (odds ratio 1.35, Pcombined = 1.03 × 10−11). The A>G variation at rs13259960, located in an intronic enhancer, was found to impair STAT1 recruitment to the enhancer that loops to the SLEAR promoter, resulting in decreased SLEAR production in peripheral blood mononuclear cells from patients with SLE (3 with the G/G genotype, 22 with A/G, and 103 with A/A at rs13259960; P = 0.0241). Moreover, SLEAR interacted with the RNA binding proteins interleukin enhancer binding factor 2, heterogeneous nuclear RNP F, and TATA‐binding protein–associated factor 15, to form a complex for transcriptional activation of the downstream antiapoptotic genes. In addition, SLEAR regulated apoptosis of Jurkat cells in vitro, and its expression level was correlated with the degree of cell death in the peripheral blood of patients with SLE (r = 0.824, P = 2.15 × 10−8; n = 30). Conclusion: These findings suggest a mechanism by which the risk variant at rs13259960 modulates SLEAR expression and confers a predisposition to SLE. Taken together, these results may give insights into the etiology of SLE. [ABSTRACT FROM AUTHOR]

By sequencing the whole gene transcriptome of IMQ-treated psoriatic mouse skin, we found a novel gene, RasGRP1, associated with psoriasis. RasGRP1 overexpression and deficiency influence IMQ-induced psoriasis-like manifestations and skin inflammation in mice. VEGF in the epidermis promotes T-cell activation through the RasGRP1-AKT-NF-κB pathway and increases the levels of psoriasis-related genes in the skin, thereby aggravating psoriatic skin inflammation. RasGRP1 is required for psoriasis development mediated by VEGF, providing a potential target for the treatment of psoriasis. [Display omitted] • RasGRP1 protein levels were significantly increased in the skin of psoriatic mice. • RasGRP1 can influence IMQ-induced skin inflammation in mice. • RasGRP1 is required for psoriasis development mediated by VEGF. • VEGF depends on RasGRP1 to aggravate psoriasis-like inflammation. The vascular endothelial growth factor (VEGF) signal transduction pathway has been shown to be a potential target for the treatment of psoriasis. Ras guanyl-releasing protein 1 (RasGRP1), a downstream target gene of VEGF, regulates the development, homeostasis, and differentiation of T cells, but the contribution of RasGRP1 to psoriasis is limited. In this manuscript, we aimed to investigate the role of RasGRP1 in psoriasis. The RNA-Seq transcriptome sequencing data from the mouse model of psoriasis treated with IMQ (imiquimod) were analyzed. The effect of RasGRP1 was investigated through in vivo injection of activators or small molecular inhibitors, as well as adeno-associated virus injections. Gene knockout and NB-UVB (narrow-band ultraviolet B) treatments were utilized to interfere with the psoriatic mouse model. By transfection of lentivirus in vitro, the effect of RasGRP1 gene function on the secretion of psoriasis-related cytokines by T cells was confirmed. We showed that cutaneous VEGF and RasGRP1 were strongly activated in human psoriatic lesions and the skin of mice with IMQ-induced psoriasis. RasGRP1 deficiency and overexpression influence IMQ-induced psoriasis-like manifestations and skin inflammation in mice. VEGF, secreted mainly by epidermal cells, mediates psoriatic inflammation through the RasGRP1-AKT-NF-κB pathway. RasGRP1 is required for psoriasis development mediated by VEGF. These results confirmed the role of RasGRP1 in the pathogenesis of psoriasis and provided potential targets for clinical psoriasis treatment. [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]

This study was aimed to investigate whether NFKB1 participates in the pathogenesis of psoriasis by mediating Th1/Th17 cells. In this study, expression of NFKB1 was assessed in skin tissues from psoriasis patients and the healthy controls through Western blot and Immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the serum levels of IFN-γ, IL-17 (IL-17A) and IL-17RA. The imiquimod-induced psoriasis mouse model was employed to examine the role of NFKB1 in psoriasis via the assessment of psoriasis area and severity index (PASI), including erythema, thickness and scales. The effects of NFKB1 on Th1/Th17 cells in were examined by flow cytometry. In vitro co-culture of Th1/Th17 cells isolated from different mice with HaCat cells was conducted to elucidate the effect of Th1/Th17 cells-mediated by NFKB1 on HaCat cells by MTT, wound healing and transwell invasion assay, respectively. The results showed that NF-κB p105/p50 expression in skin tissues was significantly increased in psoriasis (n = 21) compared to the healthy controls (n = 16), as well as levels of serum INF-γ and IL-17. Additionally, NF-κB p105/p50 expression in lesional skin tissues was much higher than that in non-lesional skin tissues of the same patients. In the psoriasis mouse model, NFKB1 overexpression significantly elevated the scores of erythema, thickness and scales. Besides, NFKB1 up-regulated the level of NF-κB p105/p50, INF-γ, T-bet, IL-17 and RORγt, as well as Th1/Th17 cells in skin tissues of psoriasis mice. Finally, in vitro assay confirmed that the activation of Th1 and Th17 mediated by NFKB1 in psoriasis promoted the proliferation, migration and invasion of keratinocytes. These findings suggest a critical role for NFKB1 in the regulation of Th1 and Th17 in psoriasis. [ABSTRACT FROM AUTHOR]

Objective This study was aimed to explore the effect of Bach2 on B cells in systemic lupus erythematosus (SLE), as well as the underlying mechanisms. Methods Expression of Bach2, phosphorylated-Bach2 (p-Bach2), Akt, p-Akt and BCR-ABL (p210) in B cells isolated from SLE patients and the healthy persons were assessed by Western blot. Immunofluorescence staining was performed to assess the localization of Bach2 in B cells. Enzyme-linked immunosorbent assay (ELISA) was employed to detect IgG produced by B cells. Cell counting kit-8 (CCK-8) and Annexin-V FITC/PI double staining assay were adopted to evaluate cell proliferation and apoptosis in B cells, respectively. Results Compared to the healthy controls, Bach2, p-Akt and p210 were significantly decreased, while nuclear translocation of Bach2, IgG, CD40 and CD86 obviously up-regulated in B cells from SLE patients. Bach2 significantly inhibited the proliferation, promoted apoptosis of B cells from SLE patients, whereas BCR-ABL dramatically reversed cell changes induced by Bach2. Besides, BCR-ABL also inhibited nuclear translocation of Bach2 in B cells from SLE patients. Further, LY294002 treatment had no effect on decreased expression of Bach2 induced by BCR-ABL, but significantly eliminated BCR-ABL-induced phosphorylation of Bach2 and restored reduced nuclear translocation of Bach2 induced by BCR-ABL in B cells from SLE. Conclusions Bach2 may play a suppressive role in B cells from SLE, and BCR-ABL may inhibit the nuclear translocation of Bach2 via serine phosphorylation through the PI3K pathway. [ABSTRACT FROM AUTHOR]

Vitiligo is an immune-related disease with patchy depigmentation of skin and hair caused by selective destruction of melanocytes. In recent decades, many studies have shown the association between vitiligo and HLA genes; however, the results of Han Chinese are scarce. In this study, we performed a fine-mapping analysis of the MHC region in 2818 Han Chinese subjects through a widely used HLA imputation method with a newly built large-scale Han-MHC reference panel. Three new four-digit HLA alleles ( HLA-DQB1  ∗  02:02 , HLA-DQA1  ∗  02:01 and HLA-DPB1  ∗  17:01 ) were identified to be associated with the risk of vitiligo, and four previously reported alleles were confirmed. Further conditional analysis revealed that two important variants, HLA-DQβ1 amino acid position 135 (OR = 1.79, P  = 1.87 × 10 −11 ) and HLA-B amino acid positions 45–46 (OR = 1.44, P  = 5.61 × 10 −11 ), conferred most of the MHC associations. Three-dimension ribbon models showed that the former is located within the β2 domain of the HLA-DQβ1 molecule, and the latter lies in the α1 domain of the HLA-B molecule, while both are involved in specific antigen presenting process. Finally, we summarized all significant signals in the MHC region to clarify their complex relationships, and 8.60% of phenotypic variance could be explained based on all reported variants in Han Chinese so far. Our findings highlight the complex genetic architecture of the MHC region for vitiligo in Han Chinese population and expand our understanding of the roles of HLA coding variants in the etiology of vitiligo. [ABSTRACT FROM AUTHOR]

Background Bullous pemphigoid (BP) is one of the most common autoimmune skin diseases. Associations of genes, especially human leukocyte antigen (HLA)-DQ alleles, with BP indicate that genetic predisposition contributes to the disease. Objectives To evaluate the association of HLA class I and HLA class II alleles with susceptibility to BP in the northern Chinese Han population. Methods We performed genotype for HLA-A, -B, -C, -G, -DPA1, -DPB1, -DQA1, -DQB1 and -DRB1 loci in 105 patients with BP by Sanger sequence-based typing (SBT) method. These data were compared with a local control cohort of 420 age- and sex-matched cases. Results Among the HLA alleles described herein, the susceptibility alleles associated with a high prevalence of BP were A*11:01 (OR = 1.9 Pc  = 0.017); B*37:01 (OR = 8, Pc  = 1.811 × 10 −6 ); G*01:01 (OR = 3.61, Pc  = 2.839 × 10 −15 ) and G*01:06 (OR = 2.22, Pc  = 0.025); DQA1*01:05 (OR = 4.87, Pc  = 5.822 × 10 −5 ), DQA1*05:05 (OR = 2.64, Pc  = 9.114 × 10 −4 ), and DQA1*05:08 (OR = 10.2, Pc  = 0.016); DQB1*03:01 (OR = 1.69, Pc  = 0.048) and DQB1*05:01 (OR = 3.42, Pc  = 7.28 × 10 −6 ); and DRB1*10:01 (OR = 6.85, Pc  = 2.63 × 10 −6 ). To the contrary, HLA-DQA1*01:02 (OR = 0.46, Pc  = 8.603 × 10 −4 ) and DQA1*01:03 (OR = 0.38, Pc  = 0.048); DQB1*02:02 (OR = 0.28, Pc  = 0.016); and DRB1*07:01 (OR = 0.26, Pc  = 0.004) had significant associations with protection against BP. In addition, the frequency of haplotype HLA-DRB1*13-DQA1*05-DQB1*03 (OR = 12.32, Pc  = 0.026) in BP patients was significantly higher than those in controls. Conclusion Our data demonstrated that the alleles and haplotypes found in this study may be important differential genetic markers for susceptibility to or protection against BP in individuals of northern Chinese Han population. [ABSTRACT FROM AUTHOR]

Background Vitiligo is an autoimmune disease, characterized by progressive loss of skin pigmentation, which is caused by the interactions of multiple factors, such as heredity, immunity and environment. Recently, a single nucleotide polymorphism (SNP) rs638893 at 11q23.3 region was identified as a risk factor for vitiligo in genome-wide association studies and multiple SNPs in this region have been associated with other autoimmune diseases. Objective This study aims to identify additional susceptibility variants associated with vitiligo at 11q23.3 in the Chinese Han population. Methods We selected and genotyped 26 SNPs at 11q23.3 in an independent cohort including 2924 cases and 4048 controls using the Sequenom MassArray iPLEX ® system. Bonferroni adjustment was used for multiple comparisons and P value <1.92 × 10 −3 (0.05/26) was considered statistically significant. Results The A allele of rs613791 and G allele of rs523604 located in CXCR5 were observed to be significantly associated with vitiligo (OR = 1.21, 95% CI: 1.11–1.31, P = 1.20 × 10 −5 ; OR = 1.14, 95% CI: 1.07–1.23, P = 1.90 × 10 −4 , respectively). The C allele of rs638893 (a previously reported one) located upstream of DDX6 was also significantly associated with vitiligo (OR = 1.25, 95% CI: 1.12–1.38, P = 3.04 × 10 −5 ). The genotypes distribution of 3 SNPs also showed significant differences between case and control (rs613791: P = 7.00 × 10 −6 , rs523604: P = 4.00 × 10 −3 , rs638893: P = 1.20 × 10 −5 , respectively). The two newly identified SNPs (rs613791 and rs523604) showed independent associations with vitiligo by linkage disequilibrium analysis and conditional logistic regression. Conclusions The study identified two new independent signals in the associated locus 11q23.3 for vitiligo. The presence of multiple independent variants emphasizes an important role of this region in disease susceptibility. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris is a chronic inflammatory skin disease associated with complex genetic susceptibility. Recently, we identified a single-nucleotide variant rs1020760 at NFKB1 significantly associated with psoriasis in a Han Chinese population in deep analysis of exome and targeted sequencing ( P = 1.76 × 10−8). To investigate the potential association between rs1020760 and phenotypes of psoriasis vulgaris, we performed a genotype-phenotype analysis. A total of 9946 cases and 9906 controls with detailed clinical and demographic information were involved in this study, while the genotype data of rs1020760 was available in the previous targeted sequencing study of psoriasis. Genotype-based association testing revealed the additive model might provide the best fit for rs1020760 ( P = 5.44 × 10−8). Case-only analysis showed that the distribution of allele G was significantly different between the cases with and without family history ( Pallele = 4.07 × 10−3, Pgenotype = 5.75 × 10−3). The differences in allele and genotype frequencies were observed between all the subphenotypes and controls except for the genotype frequency of the late onset subgroup, while no difference was found in case-only analysis for the other two subphenotypes. Rs1020760 was preferentially associated with family history of psoriasis, implying that NFKB1 might not only play important roles in the development of psoriasis, but might also contribute to the special phenotypes of this disease. [ABSTRACT FROM AUTHOR]

Melanoma, the most aggressive form of skin cancer, causes more than 40,000 deaths each year worldwide. And epidermoid carcinoma is another major form of skin cancer, which could be studied together with melanoma in several aspects. Asparagine synthetase (ASNS) gene encodes an enzyme that catalyzes the glutamine- and ATP-dependent conversion of aspartic acid to asparagine, and its expression is associated with the chemotherapy resistance and prognosis in several human cancers. The present study aims to explore the potential role of ASNS in melanoma cells A375 and human epidermoid carcinoma cell line A431. We applied a lentivirus-mediated RNA interference (RNAi) system to study its function in cell growth of both cells. The results revealed that inhibition of ASNS expression by RNAi significantly suppressed the growth of melanoma cells and epidermoid carcinoma cells, and induced a G0/G1 cell cycle arrest in melanoma cells. Knockdown of ASNS in A375 cells remarkably downregulated the expression levels of CDK4, CDK6, and Cyclin D1, and upregulated the expression of p21. Therefore, our study provides evidence that ASNS may represent a potential therapeutic target for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Objective Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. Methods Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. Results More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. Conclusion Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes. [ABSTRACT FROM AUTHOR]

Skin cancer is the most common malignancy with increasing incidence rates worldwide. The advanced form of skin cancer, melanoma, is resistant to conventional treatment methods, which motivated researchers to identify an alternative effective therapeutic approach. This study was designed to identify the effects of small interfering RNA (si-RNA) mediated silencing of eukaryotic translation initiation factor 3, subunit D (EIF3D) against melanoma cell survival. Briefly, a lentivirus-mediated RNA interference system was employed to knock down EIF3D expression in A375 and A431 melanoma cells. The cell proliferation was analyzed by methylthiazoletetrazolium (MTT) and colony formation assays. The cell cycle progression was investigated using flow cytometry. Results revealed that si-RNA-mediated knockdown of EIF3D significantly reduced the gene and protein expression levels of EIF3D in melanoma cells. Furthermore, knockdown of EIF3D led to a significant reduction in cell proliferation due to G2/M phase cell cycle arrest. Apparently, the study demonstrated the critical involvement of EIF3D in the survival and progression of melanoma cells and depletion of EIF3D could be developed as a possible therapeutic option in the gene-targeted treatment of melanoma. [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]

Psoriasis is a chronic skin disorder with undefined pathogenesis. Several biomarkers for this disease have been identified by proteomic analysis. We explored the whole-proteomic changes in 45 pairs of psoriatic and adjacent noninvolved skin tissues in a Chinese population. A total of 3686 proteins were identified, of which 3008 were quantified. A total of 102 and 124 proteins were upregulated and downregulated in lesional skin, respectively. SART1 (P = 3.55 × 10−5) and GLTP (P = 1.54 × 10−3) were the most significantly down- and upregulated proteins. Nearly 90% of these differentially regulated proteins exhibited the same expression trends as those in an online RNA sequencing dataset for psoriasis; 19 differentially regulated proteins exhibited a negative relationship with DNA methylation data for psoriatic lesions. The differentially expressed proteins were enriched in ribosomes, antigen processing and presentation, immune response, and IL-17 signalling pathways. This study identified multiple differentially regulated proteins in psoriatic lesions, which suggested that changes in the proteome play important regulatory roles in psoriasis-associated processes. Proteomic analysis was performed in 45 pairs of psoriatic and adjacent noninvolved skin tissues in a Chinese population. More than 3000 proteins were quantified, of which 226 were differentially expressed in psoriatic skin tissues. These proteins were mainly enriched in the immune response, antigen processing and presentation and IL-17 signalling pathways, which have been reported to be associated with the pathogenesis of psoriasis. Graphical abstract [Display omitted] • The technology of TMT labeling and LC-MS/MS was used to explore DEPs in skin lesions in a Chinese population. • A total of 3008 proteins were quantified, among which 102 and 124 were up- and down-regulated in psoriatic lesions. • Antigen processing and presentation, ribosome and IL-17 signalling were enriched with up-regulated proteins. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified over 120 risk loci for psoriasis. However, most of the variations are located in non-coding region with high frequency and small effect size. Pathogenetic variants are rarely reported except HLA-C*0602 with the odds ratio being approximately 4.0 in Chinese population. Although rare variations still account for a small proportion of phenotypic variances in complex diseases, their effect on phenotypes is large. Recently, more and more studies focus on the low-frequency functional variants and have achieved a certain amount of success. Whole genome sequencing and sanger sequencing was performed on 8 MZ twin pairs discordant for psoriasis to scan and verified the de novo mutations (DNMs). Additionally, 665 individuals with about 20 years' medical history versus 2054 healthy controls and two published large population studies which had about 8 years' medical history (including 10,727 cases versus 10,582 controls) were applied to validate the enrichment of rare damaging mutations in two DNMs genes. Besides, to verify the pathogenicity of candidate DNM in C3 , RNA-sequencing for CD4+, CD8+ T cells of twins and lesion, non-lesion skin of psoriasis patients were carried out. Meanwhile, the enzyme-linked immunosorbent assay kit was used to detect the level of C3, C3b in the supernatant of peripheral blood. A total of 27 DNMs between co-twins were identified. We found six of eight twins carry HLA-C∗0602 allele which have large effects on psoriasis. And it is interesting that a missense mutation in SPRED1 and a splice region mutation in C3 are found in the psoriasis individuals in the other two MZ twin pairs without carrying HLA-C*0602 allele. In the replication stage, we found 2 loss-of-function (LOF) variants of C3 only in 665 cases with about 20 years' medical history and gene-wise analysis in 665 cases and 2054 controls showed that the rare missense mutations in C3 were enriched in cases (OR = 1.91, P = 0.0028). We further scanned the LOF mutations of C3 in two published studies (about 8 years' medical history), and found one LOF mutation in the case without carrying HLA-C*0602. In the individual with DNM in C3 , RNA sequencing showed the expression level of C3 in skin was significant higher than healthy samples in public database (TPM fold change = 1.40, P = 0.000181) and ELISA showed protein C3 in peripheral blood was higher (~2.2-fold difference) than the other samples of twins without DNM in C3. To the best of our knowledge, this is the first report that DNM in C3 is the likely pathological mutations, and it provided a better understanding of the genetic etiology of psoriasis and additional treatments for this disease. • Multi-omics difference of psoriasis dis-concordance monozygotic twins are compared. • HLA allele which have large effects on psoriasis were observed on six of our twins. • Loss-of-function variants of C3 are found in psoriasis.. • De novo mutation is contributed to psoriasis.. [ABSTRACT FROM AUTHOR]

Lysine 2-hydroxyisobutyrylation is a newly discovered posttranslational modification. Although this modification is an important type of protein acylation, its role in psoriasis remains unstudied. We compared lesional and nonlesional psoriasis skin samples from 45 psoriasis patients. The result showed that this highly conserved modification was found in large quantities in both normal and diseased dermal tissues. However, there were a number of clear and significant differences between normal and diseased skin tissue. By comparing, lysine 2-hydroxyisobutyrylation was upregulated at 94 sites in 72 proteins and downregulated at 51 sites in 44 proteins in lesional skin. In particular, the sites with the most significant downregulation of lysine 2-hydroxyisobutyrylation were found in S100A9 (ratio = 0.140, p -value =.000371), while the most upregulated site was found in tenascin (ratio = 3.082, p-value =.0307). Loci associated with psoriasis, including FUBP1, SERPINB2 and S100A9, also exhibited significant regulation. Analyses of proteome data revealed that SERPINB2 and S100A9 were differentially expressed proteins. And bioinformatics analysis suggest that the P13K-Akt signaling pathway was more enriched with lysine 2-hydroxyisobutyrylation in lesional psoriasis skin. Our study revealed that lysine 2-hydroxyisobutyrylation is broadly present in psoriasis skin, suggesting that this modification plays a role in psoriasis pathogenesis. A newly discovered protein posttranslational modification, lysine 2-hydroxyisobutyrylation, has been found to occur in a wide variety of organisms and to participate in some important metabolic processes. In this study, lysine 2-hydroxyisobutyrylation in lesional psoriasis skin and nonlesional psoriasis skin was quantified and compared for the first time. We found a number of differentially modified proteins and sites in our comparisons. Interestingly, some of the identified proteins and pathways with significantly different modifications, such as S100A9 and the PI3K-Akt signaling pathway, have been previously reported to be associated with psoriasis. We hope that this research will provide new insights into psoriasis. Unlabelled Image • For the first time, the occurrence of K hib in skin tissues from patients with psoriasis was quantified and detected. • Significant differences in K hib between lesional psoriasis skin and nonlesional psoriasis skin were found. • Many of the differentially modified proteins we found have previously been reported to be associated with psoriasis. • The results of this study will provide new insights for studies on psoriasis in the future. [ABSTRACT FROM AUTHOR]

Background: Psoriasis (Ps) is a common chronic inflammatory skin disease. The keratinocytes of psoriatic skin defy normal apoptosis and exhibit active cell proliferation. Aberrant DNA methylation (DNAm) has been suggested relevant through regulating the expression of Ps susceptibility genes. However, it is unclear whether the biological age inferred from DNA methylome is affected. Results: To address the above issue, we applied a recently developed methylation clock model to our Chinese Han population dataset, which includes DNAm data of 114 involved psoriatic skin tissues (PP) and 41 uninvolved psoriatic skin tissues (PN) from Ps patients, and 62 normal skin tissues (NN) from health controls. We first confirmed the applicability of the clock in PN and NN. We then showed that PP samples have largely unchanged DNAm age, and that no association was observed between available clinical features and DNAm age acceleration. Examination of genome-wide CpGs yielded age-associated CpGs with concordant age-association coefficients among the three groups, which was also supported by an external dataset. We also interestingly observed two clock CpGs differentially methylated between PP and PN. Conclusions: Overall, our results suggest no significant alteration in DNAm age in PN and PP. Therefore, the increase in keratinocyte proliferation and alteration in DNAm caused by Ps may not affect the biological age of psoriatic skin tissue. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 23-year-old man with skin-colored papules and nodules of various sizes on face. A typical histological characteristics consistent with trichoepithelioma by a skin biopsy. A novel mutation of the CYLD gene was identified in a Chinese Multiple Familial Trichoepithelioma (MFT) family. Dysregulated tropomyosin kinase signalling is discussed.

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]