Mosaic GJB2 mutations in widespread porokeratotic adnexal ostial nevus: Report of two patients.

Porokeratotic adnexal ostial nevus (PAON) is a rare adnexal hamartoma characterized by keratotic papules following Blaschko's lines, typically located on the unilateral distal extremities. Cutaneous somatic GJB2 mutations have been linked to the pathogenesis of PAON. However, the genetic mechanism underlying bilateral or extended forms, which are less documented, remains unknown. In this study, we presented two cases of PAON with widespread cutaneous lesions and scalp involvement, and demonstrated the presence of GJB2 mosaic mutations in both patients. We further investigated the mosaic frequency in different tissues to gain insights into the mutation events contributing to the phenotype of widespread PAON. Our findings suggest that early postzygotic mutation causing mosaic GJB2 mutations may contribute to the widespread phenotype of PAON, thereby enriching the disease spectrum and mutation profile of PAON.

AQP5 pathogenic variants induce palmoplantar keratoderma Bothnia type in two Chinese families.

Palmoplantar keratoderma Bothnia type (PPKB) is caused by AQP5 pathogenic variants. The mechanisms of this disease and the genotype-phenotype correlation are still not fully understood. We report two pedigrees with PPKB caused by a recurrent variant c.367A>T and a novel variant c.530T>A in the AQP5 gene, respectively. We also summarize the cases with AQP5 variants identified, and found that there seemed to be no significant genotype-phenotype correlation of this disease. Moreover, we noticed that the epidermis of the patient had strong proliferation and immature differentiation potential as well as recognizing the possible important role of TRPV4 in the pathogenesis of PPKB.

Association of Polymorphisms of Metabolism-Related Genes with Psoriasis Vulgaris in Han Chinese.

AIM: Psoriasis is a chronic inflammatory disease with a complex etiology, and psoriasis vulgaris (PsV) is the most common type of psoriasis. Recent studies suggest the relationship between psoriasis and metabolic syndrome in different ethnicities. This study is aimed at evaluating the association of metabolism-related gene variants with the risk of PsV in Chinese Han population. Material and Methods. PsV patients (1030) and healthy controls (965) were enrolled in this study. Eighteen single-nucleotide polymorphisms (SNPs) previously reported to be significantly associated with metabolic syndrome were selected. SNPs were detected by next-generation sequencing. RESULTS: Seven SNPs were significantly associated with PsV: rs805303 (P = 0.012, OR = 0.85), rs3177928 (P = 1.37 × 10-15, OR = 2.51), and rs2247056 (P = 3.73 × 10-4, OR = 0.67) located in the HLA gene region; rs1047781 (P = 0.012, OR = 1.18), rs281379 (P = 0.014, OR = 1.71), and rs492602 (P = 0.005, OR = 1.86) located in the FUT2 region; and rs2303138 (P = 0.014, OR = 1.18) located in the LNPEP region. After stratified analysis, rs805303 (P = 0.017, OR = 0.74) and rs2303138 (P = 0.041, OR = 1.30) were associated with PsVs when HLA-C∗06 : 02 was positive, and rs805303 (P = 5.62 × 10-5, OR = 0.68), rs3177928 (P = 0.003, OR = 1.75), rs281379 (P = 0.034, OR = 1.96), and rs492602 (P = 0.025, OR = 2.04) were associated with PsVs when HLA-C∗06 : 02 was negative. CONCLUSION: PsV and metabolic syndrome may have overlapped susceptible genes in Chinese Han population.

Effect of Gentamicin Ointment in Patients with Nagashima-type Palmoplantar Keratosis: A Double-blind Vehicle-controlled Study.

Gentamicin ointment has potential in the treatment of Nagashima-type palmoplantar keratosis. However, there is a lack of reliable study data. The aim of this study was to perform a prospective, randomized, double-blinded, contralateral, vehicle-controlled clinical trial. A total of 20 subjects diagnosed with Nagashima-type palmoplantar keratosis by genetic test, who carried nonsense mutations, enrolled in the 30-day study. Gentamicin ointment was applied to the hand and foot on one side of the body, and vehicle ointment was applied to the hand and foot on the other side. The choice of hand and foot in each subject was randomly allocated. The severity of the patient's skin lesions and quality of life were assessed by a blinded evaluator, using the Dermatology Life Quality Index, visual analogue scale scores and digital photography. Gentamicin ointment treatment resulted in a significant improvement in symptoms of hyperkeratosis and foul smell compared with vehicle. No difference was found in the effect on erythema between gentamicin and vehicle. In conclusion, gentamicin ointment demonstrated positive responses and good tolerance in treating Nagashima-type palmoplantar keratosis caused by nonsense mutations.

Study on the psychological health and related risk factors in 245 patients with psoriasis in Inner Mongolia.

To investigate the psychological health and related risk factors in patients suffering from psoriasis. A total of 245 inpatients and outpatients with psoriasis were selected from January 2014 to December 2015. Patients with psoriasis were assessed a homemade questionnaire as well as the Psoriasis Area and Severity Index (PASI), Selfrating Anxiety Scale, Self-rating Depression Scale, Trait Coping Style Questionnaire and Social Avoidance and Distress Scale.Differences in sex, age, marital status, type of medical payment, occupation, economic situation, disease severity, and type of psychological state of psoriasis patients were significant, there was no significant difference in psychological health between psoriasis patients with different levels of educational attainment. Scores for anxiety, depression, social avoidance, and social distress were positively correlated with disease severity and negative-coping scores, but a significant negative correlation was observed with scores for social support and positive coping. Stepwise regression analysis of factors influencing psychological health showed that total social support and negative-coping scores could explain 65.2% of the variation. Patients with psoriasis can suffer from anxiety, depression, social distress, and social avoidance. Physicians should pay greater attention to deterioration in mental health of psoriasis patients.

Association between LCE gene polymorphisms and psoriasis vulgaris among Mongolians from Inner Mongolia.

The late cornified envelope (LCE) gene cluster is located on chromosome 1q21, including LCE1-LCE6. Several single nucleotide polymorphisms (SNPs) in the LCE cluster were associated with susceptibility to psoriasis in Chinese population. However, there is no report on the relationship in ethnic minority areas in China. This study aimed to investigate the association between the gene polymorphisms of LCE1B, LCE1C, LCE3A, LCE3D and psoriasis vulgaris among Mongolians from Inner Mongolia. Totally, 305 Mongolians with psoriasis vulgaris (PsV) and 383 healthy controls were enrolled in the study from 2006 to 2015. 7 SNPs including rs6701216, rs4112788, rs12023196, rs512208, rs4845454, rs4085613 and rs1886734, were selected for genotyping with ligase detection reaction (LDR). Statistical analysis was performed for comparisons of allele frequencies and genotype frequencies between the patient group and the control group. In this study, excluding rs4085613 and rs1886734, differences were detected in the allele frequencies of other 5 SNPs between the patients and controls. Genotype analysis showed that under the recessive inheritance model, the genotype frequencies of rs4845454, rs4112788 differed between the patients and controls (all p < 0.00 5).Under the dominant and the recessive model, the genotype frequencies of rs6701216, rs12023196 and rs512208 significantly differed between the patients and controls. The LD analysis showed that strong LD existed between rs6701216 and rs12023196, rs4845454 and rs4085613, rs4845454 and rs1886734, and rs4085613 and rs1886734. The SNPs rs6701216, rs4112788, rs12023196, rs512208 and rs4845454 in the LCE gene were associated with psoriasis vulgaris among Mongolians from Inner Mongolia.

Tumor Necrosis Factor-alpha Induced Protein 3 Interacting Protein 1 Gene Polymorphisms and Pustular Psoriasis in Chinese Han Population.

BACKGROUND: Psoriasis is a common immune-mediated inflammatory dermatosis. Generalized pustular psoriasis (GPP) is the severe and rare type of psoriasis. The association between tumor necrosis factor-alpha induced protein 3 interacting protein 1 (TNIP1) gene and psoriasis was confirmed in people with multiple ethnicities. This study was to investigate the association between TNIP1 gene polymorphisms and pustular psoriasis in Chinese Han population. METHODS: Seventy-three patients with GPP, 67 patients with palmoplantar pustulosis (PPP), and 476 healthy controls were collected from Chinese Han population. Six single nucleotide polymorphisms (SNPs) of the TNIP1 gene, namely rs3805435, rs3792798, rs3792797, rs869976, rs17728338, and rs999011 were genotyped by using polymerase chain reaction-ligase detection reaction. Statistical analyses were performed using the PLINK 1.07 package. Allele frequencies and genotyping frequencies for six SNPs were compared by using Chi-square test, odd ratio (OR) (including 95% confidence interval) were calculated. The haplotype analysis was conducted by Haploview software. RESULTS: The frequencies of alleles of five SNPs were significantly different between the GPP group and the control group (P ≤ 7.22 × 10-3), especially in the GPP patients without psoriasis vulgaris (PsV). In the haplotype analysis, the most significantly different haplotype was H4: ACGAAC, with 13.1% frequency in the GPP group but only 3.4% in the control group (OR = 4.16, P = 4.459 × 10-7). However, no significant difference in the allele frequencies was found between the PPP group and control group for each of the six SNPs (P > 0.05). CONCLUSIONS: Polymorphisms in TNIP1 are associated with GPP in Chinese Han population. However, no association with PPP was found. These findings suggest that TNIP1 might be a susceptibility gene for GPP.

A large-scale screen for coding variants predisposing to psoriasis.

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

One novel susceptibility locus associate with systemic lupus erythematosus in Chinese Han population.

The aim of the study is to explore additional susceptibility factors for systemic lupus erythematosus (SLE) in Chinese Hans. Based on our previous GWAS of SLE, we performed a multistage replication study involving 3,152 cases and 7,050 controls from China to identify additional susceptibility loci for SLE by using the Sequenom MassArray system. All Chinese Han samples used in this study were obtained from doctors through collaboration with multiple hospitals in two geographic regions (central and southern China). Single-marker association analyses were performed using logistic regression with gender as a covariate in each case-control cohort. The joint analysis of all combined samples was performed using logistic regression with gender and sample cohorts as covariates. The significant association evidence for rs906868 (OR = 1.14, 95% CI 1.08-1.20, P combined = 7.71 × 10(-10)) and rs7579944 (OR = 1.13, 95% CI 1.07-1.19, P combined = 5.55 × 10(-9)) was observed, which located at 2p23.1. In this region, limb bud and heart development homolog (LBH) was the only gene indicated, suggesting LBH might be a susceptibility gene for SLE, although its function was still unknown. The results indicated that the SNP rs7579944, rs906868 at 2p23.1 showed significant association with SLE. The genes LBH which located in this loci might be the predisposing genes of SLE.

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.

[Current status of genome-wide association study].

In past five years, genome-wide association study (GWAS) has proven to be a powerful and efficient study design in identifying genetic variants associated with complex diseases and traits. Many studies have been performed to explore the genetic basis of various complex diseases and traits. Genetic breakthroughs have been achieved in complex diseases and traits, such as oncology, diabetes, cardiology, psychiatric disorders, autoimmune and immune related diseases, height, weight, blood lipid, and pigmentation. Up to September 11th 2010, nearly 200 complex diseases and traits have been investigated by this approach, and more than 3000 diseases and/or traits related variants have been identified. In this review, we present an overview of GWAS in complex diseases and traits.

A single-nucleotide polymorphism of the TNFSF4 gene is associated with systemic lupus erythematosus in Chinese Han population.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single-nucleotide polymorphisms (SNPs) in tumor necrosis factor (TNF) superfamily gene TNFSF4 have been shown to be associated with SLE in European and Hong Kong Chinese populations. But it is unknown whether it is also associated with the disease in Mainland Chinese Han population. We genotyped the SNPs rs1234315 near the TNFSF4 gene in 1,344 SLE patients and 4,315 controls of Chinese Han population and confirmed the association between the SNP and the SLE [odds ratios (ORs) of 1.45 and P values of 1.5 × 10(-16)]. The stratification analyses showed that rs1234315 was more strongly associated with SLE patients with arthritis. Our study not only suggested that the TNFSF4 gene was associated with SLE in Chinese Han population, but also implied that it might be a common genetic factor predisposing to the development of SLE in multiple populations.

Polymorphisms at 16p13 are associated with systemic lupus erythematosus in the Chinese population.

BACKGROUND: Chromosomal region 16p13 has been reported to harbour variants associated with several autoimmune diseases, including type I diabetes, rheumatoid arthritis and multiple sclerosis. OBJECTIVE: To test whether variants in the 16p13 region are also associated with systemic lupus erythematosus (SLE) by performing a candidate locus study in the Chinese Han population. METHODS: Tag single nucleotide polymorphisms (SNPs) encompassing 50 kb upstream and downstream of the 250 kb linkage disequilibrium block, previously implicated in several autoimmune diseases, were analysed in 1047 patients with SLE and 1205 controls. The SNP showing the strongest association with SLE was then replicated in an independent cohort of 1643 cases and 5930 controls. RESULTS AND CONCLUSIONS: The association between SNP rs12599402 and SLE reached the genome-wide significance level (p<5 × 10⁻8). The SNP was likely to tag the same functional variant as previously reported in European populations. The results suggested that the chromosomal region at 16p13 contains common susceptibility genes for different immune-mediated disorders.

Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus.

OBJECTIVE: We have performed a large-scale replication study based on our previous genome-wide association study (GWAS) of SLE in the Chinese Han population to further explore additional genetic variants affecting susceptibility to SLE. METHODS: Thirty-eight single nucleotide polymorphisms from our GWAS were genotyped in two additional Chinese Han cohorts (total 3152 cases and 7050 controls) using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate. RESULTS: Association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4199 cases and 8255 controls of Chinese Han [rs16972959: odds ratio (OR) = 0.81; 95% CI 0.76, 0.87; P(combined) = 1.35 × 10(-9); rs12676482: OR = 1.26; 95% CI 1.15, 1.38; P(combined) = 6.68 × 10(-7)). PRKCB is related to the established SLE immune-related pathway (NF-κB) and 8p11.21 contains important candidate genes such as IKBKB and DKK4. IKBKB is a critical component of NF-κB and DKK4 is an inhibitor of canonical Wnt signalling pathway. Interestingly, PRKCB is required for recruiting IKBKB into lipid rafts, up-regulating NF-κB-dependent survival signal. CONCLUSIONS: Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.

Down-regulated expression of IKZF1 mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with complex genetic inheritance. IKZF1 was established as a new susceptibility gene for SLE in a recent genome-wide association study (GWAS) in Chinese Han population. In order to examine whether expression levels of IKZF1 contribute to the pathogenesis of SLE, we estimated IKZF1 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) via fluorescent quantitative reverse transcription polymerase chain reaction (RT-PCR) in 60 patients with SLE and 60 controls. We also explored whether the IKZF1 mRNA expression levels are associated with the variant of the SNP rs4917014 and the SLE Disease Activity Index (SLEDAI). The expression levels of IKZF1 mRNA in patients with SLE were significantly decreased compared with those in healthy controls (P<0.001). No significant differences were found between IKZF1 mRNA expression levels and SLEDAI scores, SNP rs4917014. Our results suggest that decreased expression of IKZF1 mRNA may be correlated with the pathogenesis of SLE.

A single-nucleotide polymorphism of the TNFAIP3 gene is associated with systemic lupus erythematosus in Chinese Han population.

Systemic lupus erythematosus (SLE) is a complex systemic disease influenced by genetic and environmental factors. The exact pathogenesis of SLE is still unknown. Recently, several genome-wide association studies (GWA) in European population have found many novel susceptibility genes for SLE including TNFAIP3. In order to examine whether TNFAIP3 is associated with SLE in Chinese Han population, we genotyped one of its non-synonymous mutation SNP rs2230926, showing significant association evidence with SLE in European population, with 1,420 cases and 4,461 controls of Chinese Han by using Sequenom MassArray system. Highly significant association between SNP rs2230926 and SLE of Chinese Han was detected [OR = 1.65, 95% confidence interval (CI): 1.392-1.986, P = 2.03 x 10(-8)]. Interestingly, rs2230926 of TNFAIP3 was also associated with arthritis, ANA and some other subphenotypes of the disease. Our findings suggest that SNP rs2230926 in the TNFAIP3 might be a common genetic factor for SLE within different populations in terms of Chinese Han and European population.

Genomewide association study of leprosy.

BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.

We performed a genome-wide association study (GWAS) of systemic lupus erythematosus (SLE) in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina Human610-Quad BeadChips and replicating 78 SNPs in two additional cohorts (3,152 cases and 7,050 controls). We identified nine new susceptibility loci (ETS1, IKZF1, RASGRP3, SLC15A4, TNIP1, 7q11.23, 10q11.22, 11q23.3 and 16p11.2; 1.77 x 10(-25) < or = P(combined) < or = 2.77 x 10(-8)) and confirmed seven previously reported loci (BLK, IRF5, STAT4, TNFAIP3, TNFSF4, 6q21 and 22q11.21; 5.17 x 10(-42) < or = P(combined) < or = 5.18 x 10(-12)). Comparison with previous GWAS findings highlighted the genetic heterogeneity of SLE susceptibility between Chinese Han and European populations. This study not only advances our understanding of the genetic basis of SLE but also highlights the value of performing GWAS in diverse ancestral populations.