GWAS of Chronic Spontaneous Urticaria Reveals Genetic Overlap with Autoimmune Diseases, Not Atopic Diseases.

Although chronic spontaneous urticaria (CSU) is a common disease, GWASs of CSU are lacking. We aimed to identify susceptibility SNPs by performing a GWAS in Chinese Han adults with CSU. The discovery cohort included 430 CSU cases and 482 healthy controls. The GWAS findings were validated in 800 CSU cases and 900 healthy controls. Genetic, functional enrichment, and bioinformatic analyses of genome-wide significant SNPs were performed to assess the association between CSU and autoimmunity or atopy. Five genome-wide significant SNPs were identified: rs434124/LILRA3, rs61986182/IGHG1/2, rs73075571/TDGF1, rs9378141/HLA-G, and rs3789612/PTPN22. The first four SNPs were in linkage disequilibrium with autoimmune-related diseases‒associated SNPs and were cis-expression quantitative trait loci in immune cells. The five SNPs-annotated genes were significantly enriched in immune processes. Higher polygenic risk scores and allele frequencies of rs3789612∗T, rs9378141∗C, and rs73075571∗G were significantly associated with autoimmune-related CSU phenotypes, including positive antithyroglobulin IgG, positive anti-FcεRIα IgG, total IgE <40 IU/ml, and positive antithyroid peroxidase IgG but not with atopic or allergic sensitized CSU phenotypes. This GWAS of CSU identifies five risk loci and reveals that CSU shares genetic overlap with autoimmune diseases and that genetic factors predisposing to CSU mainly manifest through associations with autoimmune traits.

Genome-wide identification of alternative splicing associated with histone deacetylase inhibitor in cutaneous T-cell lymphomas.

Cutaneous T-cell lymphomas (CTCLs) are a kind of non-Hodgkin lymphoma that originates from skin, which is difficult to treat with traditional drugs. Human histone deacetylase inhibitors (HDACi) targeted therapy has become a promising treatment strategy in recent years, but some patients can develop resistance to the drug, leading to treatment failure. There are no public reports on whether alternative splicing (AS) and RNA binding proteins (RBP) affect the efficacy of targeted therapy. Using data from the Gene Expression Omnibus (GEO) database, we established a co-change network of AS events and RBP in CTCLs for the first time, and analyzed the potential regulatory effects of RBP on HDACi-related AS events. The dataset GSE132053, which contained the RNA sequence data for 17 HDACi samples, was downloaded and clean reads were aligned to the human GRCh38 genome by hierarchical indexing for spliced alignment of the transcripts, allowing four mismatches. Gene expression levels were evaluated using exons per million fragments mapped for each gene. Student's t-tests were performed to evaluate the significance of changes in ratios for AS events, and regulated alternative splicing events (RASEs) were defined as events with p values less than 0.05. To sort the differentially expressed genes functional categories, Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were identified using the KOBAS 2.0 server. The regulatory mechanisms of the RASEs and RBPs were evaluated using Pearson's correlation coefficient. Seven indirect events of HDACi resistance or sensitivity were identified: NIR_5151_RP11-977G19.10, NIR_4557_IRAG2, NIR_11870_SUMO1, NIR_5347_ING4, NIR_17935_DNAJC2, NIR_17974_CBLL1, and NIR_422_SLC50A1. The potential regulatory relationships between RBPs and HDACi-sensitive RASEs were also analyzed. LEPR and HNRNPAO significantly affected NIR_11870_SUMO1, suggesting a potential regulatory relationship. Additionally, CNN1 may regulate NIR_5347_ING4, CNOT3 may regulate NIR_17935_DNAJC2, and DQX1 and LENG9 may regulate NIR_422_SLC5A1. Overall, our findings establish a theoretical foundation for the precise targeted treatment of CTCLs with HDACi.

IgE and IgG Anti-Thyroid Autoantibodies in Chinese Patients With Chronic Spontaneous Urticaria and a Literature Review.

Immunoglobulin (Ig) E and IgG anti-thyroid autoantibodies (AAbs) play important roles in the immunopathogenesis of chronic spontaneous urticaria (CSU). To date, association of IgE and IgG AAbs with Chinese CSU patients has not been fully investigated. We aimed to explore prevalence rates of IgE and IgG AAbs in Chinese CSU patients and their association with clinical and laboratory parameters. Serum IgE and IgG AAbs against thyroid peroxidase (TPO) and thyroglobulin (TG), total IgE (tIgE) and specific IgEs were measured using enzyme-linked immunosorbent assay, chemiluminescence microparticle immunoassay and immunoblotting. Meta-analyses and literature review were conducted. The meta-analyses indicated that CSU cases were 4.98, 6.90 and 6.68 times more likely to have positive anti-TPO IgE, anti-TPO IgG and anti-TG IgG (all P < 0.001) compared with controls, respectively, and revealed a positive correlation between the prevalence rates of anti-TPO IgE and anti-TPO IgG (r = 0.53, P = 0.025). A total of 1,100 Chinese Han adult CSU patients and 1,100 ethnicity-, age- and sex-matched healthy controls were recruited from 15 centers. Prevalence rates of anti-TPO IgE, anti-TPO IgG, anti-TG IgE or anti-TG IgG in the patients were all significantly higher than those in the controls. Significant correlations were observed between prevalence rates of anti-TPO IgE and anti-TPO IgG (r = 0.297, P < 0.001) as well as between those of anti-TG IgE and anti-TG IgG in the patients (r = 0.137, P < 0.001). Patients with anti-TPO IgE or anti-TPO IgG had significantly lower tIgE levels (P < 0.001). Positive anti-TPO IgE, positive anti-TPO IgG and tIgE < 40 IU/mL were independent predictors of antihistamine-refractory cases. In conclusion, the prevalence rates of IgE and IgG AAbs in Chinese CSU patients are significantly elevated and reciprocally correlated. This study verifies the results of previous case-control studies of CSU patients from other populations and ethnicities.

Association of rs610604 in TNFAIP3 and rs17728338 in TNIP1 gene polymorphisms with psoriasis susceptibility: a meta-analysis of case-control studies.

BACKGROUND: To date, the fundamental pathophysiology underlying the occurrence and progression of psoriasis are still unanswered questions. Genome-wide association surveys have revealed that TNFAIP3 and TNIP1 were key biomarkers for psoriasis. Here, we intended to conduct a survey on the association between TNFAIP3 and TNIP1 gene polymorphisms and psoriasis risk. METHODS: A comprehensive search of four online databases-China National Knowledge Infrastructure (CNKI), PubMed, Embase, and Cochrane Library was undertaken up to August 25, 2019. We chose allele genetic model to deal with the original data. Newcastle-Ottawa scale (NOS) was used to evaluate the risk bias of each study. The RevMan 5.3 software was used to calculate the combined odds ratio and 95% confidence interval. RESULTS: In total, we included 13 case-control studies consist of 13,908 psoriasis patients and 20,051 controls in this work. Our results demonstrated that rs610604 in TNFAIP3 polymorphism was significantly associated with psoriasis risk using random-effect model (G vs. T, OR = 1.19, 95% CI: 1.09-1.31, P = 0.0002), and a significant association between rs17728338 in TNIP1 polymorphism and psoriasis vulnerability using fixed-effect model (A vs. G, OR = 1.69, 95% CI:1.58-1.80, P < 0.00001). CONCLUSIONS: Our findings indicated that rs610604 in TNFAIP3 and rs17728338 in TNIP1 gene polymorphisms were associated with psoriasis susceptibility.

Association of Interleukin-23R Gene Polymorphisms with Behcet's Disease Susceptibility: A Meta-Analysis of Case-control Studies.

BACKGROUND: The pathological mechanisms associated with the occurrence and development of Behcet's disease (BD) are not yet known. Two large genome-wide association surveys revealed an association between interleukin (IL)-23R single nucleotide polymorphism and BD. This study aimed to investigate the association between IL-23R gene polymorphisms and BD susceptibility. METHODS: Comprehensive literature search was performed across four online databases - PubMed, Embase, Cochrane Library, and Web of science. The included studies had to be published before May 15, 2019. The Newcastle-Ottawa scale was used to assess the quality of every included study, and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using the allele model of inheritance to evaluate the potential associations between IL-23R gene polymorphisms and BD risk. RESULTS: In all, 12 case-control studies comprising 6,926 BD patients and 10,211 controls were identified and included in this meta-analysis, in which 5 loci of IL-23R gene polymorphisms were investigated. Of these 5 loci, 2 were found to be significantly associated with BD susceptibility: rs17375018 (G vs. A, OR = 1.50, 95% CI: 1.34-1.68, P < .00001) and rs924080 (T vs. C, OR = 1.36, 95% CI: 1.29-1.43, P < .00001). Only a systematic review was conducted for rs12119179, rs11209032, and rs12141431, owing to the lack of sufficient data. CONCLUSION: This meta-analysis indicated that rs17375018 (G/A) and rs924080 (T/C) were associated with BD susceptibility. However, association of the other IL-23R polymorphisms could not be estimated owing to the lack of studies. ABBREVIATIONS: BD: Behcet's disease; SNP: single nucleotide polymorphism; HLA: human leukocyte antigen; IL: interleukin; OR: odds ratio; CI: confidence interval; HWE: Hardy-Weinberg equilibrium; UK: United Kingdom; NOS: Newcastle-Ottawa scale; GWAS: genome-wide association study; TNF-α: tumor necrosis factor-α.

Bowen's disease on the palm: A case report.

BACKGROUND: Bowen's disease (BD) is a persistent, progressive intraepidermal carcinoma. BD usually occurs in areas exposed to sunlight. Involvement of the dorsum of the hand is not rare, but that of the palmar aspect is very unusual. Only a few cases have been reported in the literature. CASE SUMMARY: Here, we report the case of a 48-year-old male patient who presented with a history of persistent local erythema lasting for 2 years on the thenar eminence of the left palm. Initially diagnosed as hand eczema, the condition did not improve with intermittent treatment with anti-allergy medications or topical glucocorticoid ointments, among other approaches. Then, the area of erythema gradually enlarged and was accompanied by mild itching. For a definite diagnosis and treatment, the patient came to our hospital. Dermoscopic examination revealed BD, and histopathological examination confirmed the diagnosis. We performed partial resection of the skin lesion followed by photodynamic therapy. No recurrence was observed at the 6-mo follow-up. CONCLUSION: For all atypical palmar lesions, early dermoscopy and/or skin biopsy are needed to avoid missed diagnosis or misdiagnosis.

The Regulatory Effects of CDKN1A on Relevant Genes in Kaposi's Sarcoma Cells.

The cyclin-dependent kinase inhibitor 1A (CDKN1A) gene plays important roles in different types of cancer; however, its mechanism in Kaposi's Sarcoma (KS) is far less known. The aim of this study is to investigate the regulatory effects of CDKN1A on relevant genes in KS cells, and ultimately determine the role of CDKN1A in KS. In the study, the CDKN1A overexpression group, or siRNA group, was transfected into KS cells, respectively. Western-Blot (WB) and quantitative real-time polymerase chain reactions (q-PCR) were performed to detect the expression of cell cycle protein D1 (CyclinD1) and cell cycle protein E (CyclinE). Q-PCR was performed to determine the expression of kshv-mir-k12-1-5p. The results prove that CDKN1A negatively regulates the expression of CyclinD1, CyclinE, and kshv-mir-k1-2-1-5p. Therefore, CDKN1A may be involved in the formation and development of KS through the regulation of kshv-mir-k12-1-5p, CyclinD1, and CyclinE. CDKN1A may become a new choice for targeted therapy in KS.

Bioinformatics analysis of key biomarkers and pathways in KSHV infected endothelial cells.

Kaposi sarcoma (KS) is an endothelial tumor etiologically related to Kaposi sarcoma herpesvirus (KSHV) infection. The aim of our study was to screen out candidate genes of KSHV infected endothelial cells and to elucidate the underlying molecular mechanisms by bioinformatics methods. Microarray datasets GSE16354 and GSE22522 were downloaded from Gene Expression Omnibus (GEO) database. the differentially expressed genes (DEGs) between endothelial cells and KSHV infected endothelial cells were identified. And then, functional enrichment analyses of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed. After that, Search Tool for the Retrieval of Interacting Genes (STRING) was used to investigate the potential protein-protein interaction (PPI) network between DEGs, Cytoscape software was used to visualize the interaction network of DEGs and to screen out the hub genes. A total of 113 DEGs and 11 hub genes were identified from the 2 datasets. GO enrichment analysis revealed that most of the DEGs were enrichen in regulation of cell proliferation, extracellular region part and sequence-specific DNA binding; KEGG pathway enrichments analysis displayed that DEGs were mostly enrichen in cell cycle, Jak-STAT signaling pathway, pathways in cancer, and Insulin signaling pathway. In conclusion, the present study identified a host of DEGs and hub genes in KSHV infected endothelial cells which may serve as potential key biomarkers and therapeutic targets, helping us to have a better understanding of the molecular mechanism of KS.

kshv-mir-k12-1-5p promotes cell growth and metastasis by targeting SOCS6 in Kaposi's sarcoma cells.

Background: Kaposi's sarcoma (KS) is a highly disseminated angiogenic tumour of endothelial cells. Many deregulated miRNAs, including kshv-mir-k12-1-5p, have been identified in KS. kshv-mir-k12-1-5p plays important roles in KS. However, the underlying mechanism is not fully understood. The aim of this study was to investigate the exact functions of kshv-mir-k12-1-5p in KS cells. Materials and methods: The biological functions of kshv-mir-k12-1-5p were studied using CCK-8, apoptosis, migration and invasion assays. Bioinformatics software was used to identify the target gene (SOCS6) of kshv-mir-k12-1-5p. A dual luciferase assay, Western blot (WB) and quantitative real-time polymerase chain reaction (q-PCR) were performed to further verify the target gene. The underlying molecular mechanisms of kshv-mir-k12-1-5p in KS cells were also explored. Results: kshv-mir-k12-1-5p can promote the proliferation, migration and invasion of KS cells and inhibit cell apoptosis. Suppressor of cytokine signalling 6 (SOCS6) was identified as a direct target of kshv-mir-k12-1-5p, and kshv-mir-k12-1-5p can downregulate SOCS6 expression. In addition, knockdown of SOCS6 rescued the effects of kshv-mir-k12-1-5p inhibitor. Hence, a direct relationship between kshv-mir-k12-1-5p and SOCS6 was confirmed. Conclusions: kshv-mir-k12-1-5p promotes the malignant phenotype of KS cells by targeting SOCS6, suggesting that kshv-mir-k12-1-5p could be a potential therapeutic target for KS.

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.

MicroRNA-126 regulates the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in SLK cells in vitro and the expression of its pathway members in Kaposi's sarcoma tissue.

In vitro, microRNA-126 (miR-126) inhibits SLK cell proliferation, inhibits the cell cycle, induces cell apoptosis, and reduces cell invasiveness. Double luciferase assays have shown that phosphatidylinositol-3 kinase (PI3K) is the miR-126 target in SLK cells. We aimed to investigate the influence of miR-126 on the phosphate and tension homology deleted on chromosome ten (PTEN)/PI3K/protein kinase B (AKT) pathway members in SLK cells and to determine the expression of these pathway members in Kaposi's sarcoma (KS). The mimic and inhibitor of miR-126 were transfected into SLK cells and PTEN and AKT1 expression was assayed in SLK cells by real-time quantitative PCR and western blotting. PTEN, AKT1, phosphorylated (P)-PTEN, and phosphorylated (P)-AKT expression in KS and paraneoplastic skin were assayed by immunohistochemistry. AKT1 expression was downregulated in SLK cells that overexpressed miR-126, while there was no significant difference in PTEN expression between SLK cells overexpressing miR-126 and those in which its expression was knocked down. PTEN and AKT1 were expressed in KS and paraneoplastic skin but P-AKT was not. Interestingly, P-PTEN was not expressed in paraneoplastic skin but it was expressed in 90% of KS biopsies (P < .05). P-PTEN expression was also significantly higher in visceral than in cutaneous KS (P = .01) and was higher in indoor than in outdoor workers (P = .018). In vitro, miR-126 negatively regulated AKT1 expression but no regulation of PTEN expression was evident. Results indicated that in KS, PTEN is activated and may therefore be a potential therapeutic target for KS. In addition, these results also indicate that sunlight may not be the cause of KS.

Differential expression of microRNAs in the normal skin of the Han and Uyghur populations in Xinjiang Province.

In this study, we investigated the expression of microRNAs (miRNAs) in the skin samples from the Han and Uyghur populations in Xinjiang, China. The miRNA levels of the normal skin samples from 10 individuals of Uyghur or Han were tested by microarray and the expression differentiations were compared. Among the 3100 probes for microarray, a total of 247 miRNAs were differentially expressed in the Han versus Uyghur population, including 76 upregulated miRNAs and 171 downregulated miRNAs. The most significantly upregulated miRNAs were miR-141-3p, miR-1915-5p, kshv-miR-K12-2-5p, and miR-222-3p. And the most significantly downregulated miRNAs included miR-1207-3p and miR-625-3p. We have confirmed the upregulation of miR-141-3p and miR-1915-5p by qRT-PCR. There were no statistical correlations in the expression of miR-141-3p or miR-1915-5p with the age or gender within each group. Interestingly, the differentially expressed miRNAs were enriched in some cancer-related pathways, such as p53, mitogen-activated protein kinase, and WNT signal pathways. Collectively, these dysregulated expressions of the miRNAs may provide a better understanding of the differences in the incidence and mortality of skin-related carcinoma between the Uyghur and Han populations in Xinjiang.

MicroRNA-126-3p suppresses cell proliferation by targeting PIK3R2 in Kaposi's sarcoma cells.

Kaposi's sarcoma is a highly vascular tumor of lymphatic endothelial origin. Many deregulated miRNAs, including miR-126-3p, have been identified in Kaposi's sarcoma tissues. miR-126-3p is the most highly endothelial-specific miRNA that regulates vascular integrity and angiogenesis. In this study, we aimed to determine the effect of miR-126-3p on Kaposi's sarcoma cells through transfection of a miRNA mimic and inhibitor. Moreover, we searched the target gene (PIK3R2) of miR-126-3p using bioinformatics software and further verified PIK3R2 using luciferase reporter assays, Real-time quantitative PCR (qRT-PCR) and western blot. The results demonstrated that miR-126-3p inhibited cell proliferation, arrested cell cycle progression, induced cell apoptosis, and inhibited cell invasion of SLK cells. The bioinformatics analysis and luciferase reporter assay revealed that PIK3R2 mRNA is a direct target of miR-126-3p. Moreover, the level of expression of the PIK3R2 gene was downregulated in SLK cells transfected with miR-126-3p siRNAs. Therefore, our data demonstrated that miR-126-3p is a tumor suppressor miRNA that acts by targeting PIK3R2 in Kaposi's sarcoma cells. These findings contribute to our understanding of the molecular mechanisms underlying Kaposi's sarcoma.

Secreted frizzled-related protein promotors are hypermethylated in cutaneous squamous carcinoma compared with normal epidermis.

BACKGROUND: The Wnt signaling pathway is abnormally activated in many human cancers. Secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and play an important role in carcinogenesis. SFRP promoter hypermethylation has often been identified in human cancers; however, the precise role of SFRPs in cutaneous squamous cell carcinoma (SCC) is unclear. METHODS: The methylation status of the SFRP family was analyzed in an age-and sex-matched case-control study, including 40 cutaneous SCC cases and 40 normal controls, using the MassARRAY EpiTYPER system. RESULTS: The methylation rate of SFRP1, SFRP2, SFRP4, and SFRP5 promoters was significantly higher in cutaneous SCC tissues than in adjacent tissue and normal skin samples. DISCUSSION: Our manuscript mainly discussed the average methylation rate of SFRPs (SFRP1, SFRP2, SFRP4, and SFRP5) promoters are significantly high in tumor tissue samples and the average CpG island methylation rate among different pathological levels of cutaneous SCC between these genes are different. CONCLUSIONS: Our findings suggest that promoter hypermethylation of SFRPs is associated with the development of carcinoma, and could be a useful tumor marker for cutaneous SCC and other types of cancers.

The expression profiles of microRNAs in Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a multicentric angioproliferative tumor of mesenchymal origin. The molecular and biologic aspects of KS are not fully understood. MicroRNAs are non-protein-coding small RNAs in the size range 19-25 nucleotides (nt) that play important roles in biological processes, including cellular differentiation, proliferation, and death. We performed a miRNA microarray analysis by detecting six paired KS and matched adjacent healthy tissues using the 7th generation of miRCURY(TM) LNA Array (v.18.0) (Exiqon) containing 3100 capture probes. We selected 10 significant differentially expressed miRNAs, which were confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in 18 paired KS and matched adjacent healthy tissue specimens. We also investigated the associations between clinical features and miRNA expression. Among the 3100 human miRNA probes in the microarrays, we identified 170 differentially expressed miRNAs (69 upregulated and 101 downregulated miRNAs) in KS versus adjacent healthy tissues. Among the most significantly upregulated miRNAs were miR-126-3p, miR-199a-3p, miR-16-5p, and the 13 KSHV-related miRNAs. The most significantly downregulated miRNAs included miR-125b-1-3p and miR-1183. Eight upregulated miRNAs, miR-181b-5p, miR-199a-3p, miR-15a-5p, miR-126-3p, miR-1297, kshv-miR-k12-12-3p, kshv-miR-k12-1-5p, and miR-16-5p, and two downregulated miRNAs, miR-125b-1-3p and miR-1183, were confirmed by qRT-PCR in 18 paired KS samples. The qRT-PCR results for 10 miRNAs were consistent with our microarray results. The miR-125b-1-3p and miR-16-5p had statistically significant associations with HHV-8 and HIV infections in KS. The results of miRNA profiling showed that KS appears to have unique expression patterns when compared with paired adjacent healthy tissues, suggesting that deregulation of miRNAs plays an important role in the progression of KS. These differentially expressed miRNAs may provide novel diagnostic and prognostic tools.

Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

Association analyses identify three susceptibility Loci for vitiligo in the Chinese Han population.

To identify susceptibility loci for vitiligo, we extended our previous vitiligo genome-wide association study with a two-staged replication study that included 6,857 cases and 12,025 controls from the Chinese Han population. We identified three susceptibility loci, 12q13.2 (rs10876864, P(combined)=8.07 × 10(-12), odds ratio (OR)=1.18), 11q23.3 (rs638893, P(combined)=2.47 × 10(-9), OR=1.22), and 10q22.1 (rs1417210, P(combined)=1.83 × 10(-8), OR=0.88), and confirmed three previously reported loci for vitiligo, 3q28 (rs9851967, P(combined)=8.57 × 10(-8), OR=0.88), 10p15.1 (rs3134883, P(combined)=1.01 × 10(-5), OR=1.11), and 22q12.3 (rs2051582, P(combined)=2.12 × 10(-5), OR=1.14), in the Chinese Han population. The most significant single-nucleotide polymorphism in the 12q13.2 locus is located immediately upstream of the promoter region of PMEL, which encodes a major melanocyte antigen and has expression loss in the vitiligo lesional skin. In addition, both 12q13.2 and 11q23.3 loci identified in this study are also associated with other autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus. These findings provide indirect support that vitiligo pathogenesis involves a complex interplay between immune regulatory factors and melanocyte-specific factors. They also highlight similarities and differences in the genetic basis of vitiligo in Chinese and Caucasian populations.

Association analyses identify six new psoriasis susceptibility loci in the Chinese population.

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.

We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined=1.48x10(-48), OR=1.90; rs9468925, Pcombined=2.21x10(-33), OR=0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined=9.72x10(-17), OR=1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.

[Mutation analysis of a Uighur family with epidermolytic palmoplantar keratoderma].

OBJECTIVE: To map and identify the disease gene for the epidermolytic palmoplantar keratoderma (EPPK) in a Uighur family of China. METHODS: Blood samples were collected and genomic DNA was extracted from 48 members of the Xinjiang Uighur family. Six microsatellite repeat sequences on chromosome region 17q12-q21 and 12q13 were selected based on the two known candidate genes KRT9 and KRT1. Two-point linkage analysis and haplotype analysis were performed. Exons and their flanking intronic sequence of the KRT9 gene were amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: Data from the marker D17S1787 suggested linkage and yielded a Lod score of 8.65 at theta=0 by using MLINK software. Genotypes and haplotypes were acquired. The disease gene of the EPPK family is located between markers 17/TG/36620115 and D17S846. Chromosome 12q13 region was excluded with the negative Lod score obtained in marker D12S96 (Lod=-infinity at theta=0). No pathogenic mutation was detected in the KRT9 gene. CONCLUSION: The disease gene of the EPPK family is located on chromosome region 17q21.2. The keratin 9 gene might not be the disease gene.