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1.
Epigenomics ; 11(4): 455-467, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30785334

RESUMO

AIM: A genomic region on 5q33.3 lies between and encompasses the IL12B and PTTG1 genes, and contains many potential psoriasis causal variants. We aimed to further examine the influence of variants in and around this region. MATERIALS & METHODS: We used least absolute shrinkage and selection operator (LASSO)-based regression analysis to assess independent contributions of 2171 variants to psoriasis susceptibility and tested them for association with different clinical psoriasis subtypes. RESULTS: We found that ADRA1B gene variants contribute to psoriasis in Chinese population. ADRA1B gene variants have a stronger association with moderate-to-severe disease group and an earlier age at onset of psoriasis than IL-12B and PTTG1 variants. CONCLUSION: The association of variants in the ADRA1B gene with psoriasis could explain why variants in the IL-12B, ADRA1B and PTTG1 gene regions are associated with psoriasis.

2.
Dermatol Ther ; 31(5): e12632, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30253049

RESUMO

To assess the efficacy, safety, and cost-effectiveness of all-trans retinoic acid/Clobetasol Propionate Compound Ointment and calcipotriol/betamethasone dipropionate ointment in the treatment of mild-to-moderate patients with psoriasis vulgaris. This was a randomized, single-blind, multicenter clinical trial. A total of 240 patients were randomized to receive twice-daily all-trans retinoic acid/Clobetasol Propionate Compound Ointment (treatment group) or once-daily calcipotriol/betamethasone dipropionate ointment (control group) for 4 weeks. The efficacy, safety, and cost-effectiveness were assessed at Weeks 2 and 4. After 4 weeks, both groups showed a significant clinical improvement compared to baseline (88.33% vs. 89.83%, respectively, p = .7112). But PASI 75 response in the treatment group was superior to the control group (44.12% vs. 28.57%, respectively, p = .0200), at Week 4. SSRI improvement rate in the treatment group was also superior to control group (67.11% vs. 59.43%, respectively, p = .0119) at Week 4. All-trans retinoic acid/Clobetasol Propionate Compound Ointment showed a significant clinical improvement in erythema, infiltration, and scales of skin lesions and PASI score compared to baseline. 1.67% of patients (treatment group) reported adverse reactions compared to 2.50% (control group) with no statistical significance. In addition, the cost-effectiveness assessment showed a higher cost-effectiveness of the treatment group compared to the control group in 4 weeks (199.25 vs. 801.51). All-trans retinoic acid/Clobetasol Propionate Compound Ointment was effective and safe in the treatment of psoriasis vulgaris with similar efficacy as calcipotriol/betamethasone dipropionate ointment and lower treatment costs.

3.
Ann Rheum Dis ; 77(3): 417, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29233832

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS: We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS: We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (pmeta <5.00×10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10-5) in ex vivo experiments. CONCLUSIONS: This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE.

4.
Gene ; 628: 281-285, 2017 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-28739399

RESUMO

BACKGROUND: Multi-ancestry genome-wide association study (GWAS) has recently identified 11 new susceptibility loci for Atopic dermatitis (AD). The replication of these new susceptibility loci in different populations should not be ignored. OBJECTIVE: To examine whether these 11 new identified susceptibility loci are also associated with AD in the Chinese Han population. METHODS: These 11 variants were imputed using our genome-wide array dataset. The selected SNPs with suggestive signals were genotyped in a large-scale replication study with a total of 4619 cases and 10,789 controls using the Sequenom Massarray system. Association analyses were performed using PLINK 1.07 software. Results were combined across our previous AD-GWAS stage and the replication stage by meta-analysis. Bioinformatic analysis was done to predict the possible causal gene. RESULTS: Of the 11 SNPs investigated, four SNPs showed suggestive association (P<0.05) in our previously published GWAS datasets. Association evidence for an intergenic variant rs112111458 at 2p13.3 with AD was replicated in Chinese Han population (P=7.37×10-7, OR=0.86), showing significance in Meta analysis of GWAS and replication study (Pmeta=8.18×10-08, OR=0.69). Further functional annotation by HaploReg indicated that transcriptional regulation activity exists at this locus for the CD207 gene in skin tissue. CONCLUSIONS: Our study confirmed a previously reported susceptibility loci in the Chinese Han population, which implicates CD207 might be a new susceptibility gene for AD and highlights the crucial role of immune responses in AD.


Assuntos
Cromossomos Humanos Par 2 , Dermatite Atópica/genética , Predisposição Genética para Doença , Variação Genética , Locos de Características Quantitativas , Adolescente , Adulto , Alelos , Antígenos CD/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Recém-Nascido , Lectinas Tipo C/genética , Masculino , Lectinas de Ligação a Manose/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
Asian Pac J Allergy Immunol ; 35(4): 196-202, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28364410

RESUMO

BACKGROUND: Atopic dermatitis (AD) and other atopic diseases often share some common genetic and pathogenic bases. Recent genome-wide association studies (GWAS) have identified several loci associated with atopic diseases, allergic sensitization and asthma in different populations. The aim of this study was to investigate whether these susceptibility loci were related to AD in Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNPs) from recent atopic diseases and allergic sensitization GWAS were genotyped in 3,013 AD patients and 5,483 healthy controls in Chinese Han population using Sequenom MassArray system. Data was analyzed with PLINK 1.07 software. RESULTS: We identified that the susceptibility loci at 5q31 (RAD50/IL13, rs2158177, P = 1.08×10-3, OR = 1.15) and 5q22.1 (TSLP, rs1837253, P = 2.66×10-3, OR = 0.91) were significantly associated with AD. Genotype-based association testing revealed that the dominant model provided the best fit for both rs2158177 (P = 3.75×10-3) and rs1837253 (P = 5.30×10-3). Pathway analysis conformed that both loci were associated with the JAK-STAT signaling pathway. CONCLUSIONS: We identified two susceptibility loci 5q31 and 5q22.1 for AD that might bear candidate genes conferring susceptibility to AD.

6.
Gene ; 617: 17-23, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28351738

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. The 5q22.1 region was found to have an association with AD in our previous genome-wide association study (GWAS). OBJECTIVE: To identify the AD susceptibility gene in 5q22.1 and observe its expression in AD tissues. METHODS: Suggestive indels from the GWAS data were genotyped in 3013 AD patients and 5075 controls from the Chinese Han population with the SequenomMassArray system. Association, Bayesian and bioinformatics analyses were used to identify possible causal indels and genes in the 5q22.1 region. Immunohistochemistry (IHC) was performed to observe protein expression in the tissues. PLINK 1.07 software was used for all statistical analyses. RESULTS: The genotyping and association analysis showed that six deletions and four SNPs were associated with AD (P<0.005). The rs11357450 (Pcombined=7.79E-04, OR=1.39, logBayes Factor=1.29) deletion located in TMEM232 was identified to be the strongest variant. Analysis of the genetic model revealed that the dominant model best described rs11357450 (P=1.96E-03, OR=1.22; 95% CI=1.07-1.37). IHC showed that the expression of TMEM232 decreased gradually from the granular layer to the basal layer in AD, but in normal tissues, this trend was reversed. Additionally, positive cytoplasm staining was found in lymphocytes around the blood vessels in AD. CONCLUSIONS: The study indicates that TMEM232 in the 5q22.1 region is the causal gene for AD in the Chinese Han population.


Assuntos
Dermatite Atópica/genética , Mutação INDEL , Proteínas de Membrana/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Lactente , Masculino , Proteínas de Membrana/metabolismo , Polimorfismo de Nucleotídeo Único
7.
Sci Rep ; 6: 29751, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27432148

RESUMO

Prevalence of atopic dermatitis (AD) is increasing worldwide. Up to date, there has been no face-to-face nation-wide study in China. We aim to explore the prevalence of clinical diagnosed AD in children aged 1-7 ys in China. Twelve metropolises were chosen from different areas of China. In each region, we selected 4-10 kindergartens and 2-5 vaccination clinics randomly. A complete history-taking and skin examination were performed by dermatologists. The definite diagnosis of AD and the severity were determined by two or three dermatologists. All criteria concerned in UK diagnosis criteria, characteristic presentation of AD and atypical manifestations were recorded in detail. A total of 13998 children from 84 kindergartens and 40 vaccination clinics were included. The prevalence of AD was 12.94% by clinical diagnosis of dermatologists overall, with 74.6% of mild AD. Comparatively, prevalence of AD based on UK diagnostic criteria was 4.76%. This is the first face-to-face nation-wide study in Chinese children aged 1-7 ys, revealing that the prevalence of AD in children is closer to that of wealthier nations.


Assuntos
Dermatite Atópica/diagnóstico , Dermatite Atópica/epidemiologia , Pele/patologia , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , China/epidemiologia , Dermatite Atópica/etnologia , Feminino , Geografia , Humanos , Lactente , Masculino , Prevalência , Fatores de Risco , Inquéritos e Questionários
8.
Asian Pac J Allergy Immunol ; 34(2): 109-14, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27007831

RESUMO

BACKGROUND: Recent genome-wide association studies (GWAS) and a meta-analysis of GWAS for atopic dermatitis (AD) have identified some AD genetic loci in European and Japanese populations. OBJECTIVE: To investigate whether some novel susceptibility loci are associated with AD in the Chinese Han population. METHODS: We first selected eight novel susceptibility loci to replicate in 2,205 AD patients and 2,116 healthy controls using the Sequenom platform. Data were analyzed with PLINK 1.07 software. RESULTS: We found that rs12634229 (3q13.2), rs7927894 (11p13.5) and rs878860 (11p15.4) showed a slight association with AD (P = 0.012, P = 0.033, P = 0.020, respectively); rs6780220 (3p21.33) was preferentially related to AD with keratosis pilaris, but did not reach the threshold of significance after correction. The frequency of rs7927894 allele T was significantly different between AD patients with a positive and negative family history of atopy. CONCLUSION: The loci rs7927894 (11p13.5) are related to AD with a positive family history of atopy in Chinese Han population, providing novel insight into the genetic pathogenesis of AD.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 11 , Dermatite Atópica/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Dermatite Atópica/diagnóstico , Dermatite Atópica/etnologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
10.
Mol Genet Genomics ; 290(4): 1493-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25711310

RESUMO

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 combined = 1.11E-15), PRKAG2 and TMEM232-SLC25A46 SNPs (rs17173197 × rs7701890, P combined = 2.22E-15), PRKAG2 and TNFRSF6B-ZGPAT SNPs (rs17173197 × rs6010620, P combined = 6.66E-16). Besides, a three-way significant interaction among PRKAG2, TMEM232-SLC25A46 and TNFRSF6B-ZGPAT SNPs (rs17173197 × rs7701890 × rs6010620, P combined = 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.


Assuntos
Dermatite Atópica/genética , Epistasia Genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteínas Quinases Ativadas por AMP/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , China , Dermatite Atópica/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Lactente , Proteínas de Filamentos Intermediários/genética , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas de Transporte de Fosfato/genética , Membro 6b de Receptores do Fator de Necrose Tumoral/genética , Adulto Jovem
11.
Nat Commun ; 5: 4331, 2014 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25006012

RESUMO

In a previous large-scale exome sequencing analysis for psoriasis, we discovered seven common and low-frequency missense variants within six genes with genome-wide significance. Here we describe an in-depth analysis of noncoding variants based on sequencing data (10,727 cases and 10,582 controls) with replication in an independent cohort of Han Chinese individuals consisting of 4,480 cases and 6,521 controls to identify additional psoriasis susceptibility loci. We confirmed four known psoriasis susceptibility loci (IL12B, IFIH1, ERAP1 and RNF114; 2.30 × 10(-20)≤P≤2.41 × 10(-7)) and identified three new susceptibility loci: 4q24 (NFKB1) at rs1020760 (P=2.19 × 10(-8)), 12p13.3 (CD27-LAG3) at rs758739 (P=4.08 × 10(-8)) and 17q12 (IKZF3) at rs10852936 (P=1.96 × 10(-8)). Two suggestive loci, 3p21.31 and 17q25, are also identified with P<1.00 × 10(-6). The results of this study increase the number of confirmed psoriasis risk loci and provide novel insight into the pathogenesis of psoriasis.


Assuntos
Antígenos CD/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Fator de Transcrição Ikaros/genética , Subunidade p50 de NF-kappa B/genética , Psoríase/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
12.
Nat Genet ; 46(1): 45-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24212883

RESUMO

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.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Adulto , Aminopeptidases/genética , Grupo com Ancestrais do Continente Asiático/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Estudos de Casos e Controles , Conexina 26 , Conexinas/genética , Feminino , Fucosiltransferases/genética , Estudo de Associação Genômica Ampla , Guanilato Ciclase/genética , Haplótipos , Humanos , Masculino , Proteínas de Membrana/genética , Antígenos de Histocompatibilidade Menor , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Receptores de Interleucina/genética , Adulto Jovem
13.
Iran J Allergy Asthma Immunol ; 12(3): 203-10, 2013 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-23893803

RESUMO

Matrix Metalloproteinases (MMPs) play an important role in gastric cancer (GC). Accumulated evidence suggests that functional MMP-1 and MMP-7 gene polymorphisms are associated with several tumors. The aim of this study was to investigate two single nucleotide polymorphisms, MMP-1 -1607 1G/2G and MMP-7 -181 A/G, and their potential relationship with GC. We examined 246 GC patients and 252 age-and sex-matched controls from Sichuan province in China. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism strategy and DNA sequencing. We also performed a meta-analysis of relevant studies, involving 1084 cases and 1721 controls, to place our findings in a broader context. No significant relationship was observed between the MMP-1 -1607 1G/2G alleles and genotypes and the risk of GC. There were significant differences in the genotypes and allele distributions of the -181 A/G polymorphism of the MMP-7 gene between cases and controls. The -181 A allele carriers had a significantly increased risk of GC compared with -181 G allele carriers (OR=3.051, 95% CI, 1.475-6.310, P=0.002), and the AA genotype of -181 A/G was associated with an increased risk of GC compared with the AG genotype (OR=3.189, 95% CI, 1.523-6.676, P=0.001). A meta-analysis of six studies also showed a significant risk of GC associated with MMP-7 polymorphism.


Assuntos
Predisposição Genética para Doença , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/enzimologia
14.
Nat Genet ; 44(10): 1156-60, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22983302

RESUMO

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.


Assuntos
Exoma , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Mutação Puntual , Poroceratose/genética , Apoptose , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Queratinócitos/fisiologia , Masculino , Linhagem , Poroceratose/patologia , Sítios de Splice de RNA
15.
PLoS One ; 7(4): e35334, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22545103

RESUMO

Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10(-4), OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P(correction) = 3.60×10(-10), OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P(correction) = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Asma/genética , Dermatite Atópica/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Loci Gênicos , Genótipo , Haplótipos , Humanos , Lactente , Masculino , Adulto Jovem
16.
Nat Genet ; 43(7): 690-4, 2011 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-21666691

RESUMO

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Dermatite Atópica/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , China/epidemiologia , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 5/genética , Dermatite Atópica/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Fatores de Risco
17.
Rheumatology (Oxford) ; 50(4): 682-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21134959

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Quinase C/genética , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , Estudos de Casos e Controles , China , Feminino , Seguimentos , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/fisiologia , Proteína Quinase C beta , Transdução de Sinais/genética , Proteínas Wnt/fisiologia
18.
Hum Immunol ; 71(4): 418-22, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19932885

RESUMO

Keloids are benign fibroproliferative dermal tumors of unknown etiology. Some studies have suggested that human HLA status might potentiate development of keloids phenotype. No report has been published about HLA class I alleles associated with keloids in Chinese Han individuals. To investigate the etiology of keloids, the polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA class I alleles in 192 patients with keloids and 252 healthy controls in a Chinese Han population. The frequencies of HLA-A*03 (6.77% vs 0%, p(c) < 10(-7)), A*25 (10.16% vs 4.56%, p(c) = 0.0111), B*07 (7.81% vs 2.58%, p(c) = 0.0080), and Cw*0802 (19.79% vs 10.32%, p(c) = 0.0004) were significantly increased in keloid patients, whereas the frequency of HLA-A*01 (18.75% vs 38.10%, p(c) < 10(-7)) was highly decreased, compared with that in healthy controls. The A*03-B*07, A*25-B*07, A*03-Cw*0802, A*25-Cw*0802, and B*07-Cw*0802 were found as high-risk haplotypes in developing keloids in this study. No extended haplotype was found to be significantly related to keloids. Through stratified analysis, the association of subgroups (single site/multiple site, severity, and family history) of keloid patients with specific HLA alleles was identified. Our data suggest these alleles may be keloids susceptibility genes or may be in close linkage with the susceptibility genes.


Assuntos
Antígenos HLA/genética , Queloide/genética , Queloide/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Queloide/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
19.
Nat Genet ; 41(11): 1234-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19838193

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Feminino , Humanos , Masculino
20.
Nat Genet ; 41(2): 205-10, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19169255

RESUMO

We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).


Assuntos
Cromossomos Humanos Par 1 , Proteínas Ricas em Prolina do Estrato Córneo/genética , Predisposição Genética para Doença , Psoríase/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Subunidade p40 da Interleucina-12/genética , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Família Multigênica , Polimorfismo de Nucleotídeo Único , Adulto Jovem
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