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1.
Epigenomics ; 11(14): 1613-1625, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31701765

RESUMO

Aim: To understand whether the anatomical location of origin plays a role in shaping the DNA methylation (DNAm) landscape of psoriatic skins. Patients & methods: A number of 108 psoriatic and 57 control skin samples were grouped based on their anatomical locations. Two group t-tests were used to identify those differentially methylated sites and regions. Target region methylation loci were validated by bisulfate conversion sequencing. The correlations of DNAm with pathological features, DNAm and gene expression were also interrogated. Results: Our analysis revealed 315 location-specific differentially methylated sites for back, 291 for the extremities and 801 for abdomen. Moreover, we observed that the extremity-specific loci cg21942490 located on HOXA9 is associated with hyperkeratosis. We further observed that HOXA5 and KIAA1949 are differential methylation regions. Conclusion: Our study shown evidence of anatomical location-dependent DNAm pattern in psoriasis skins, and thus provided new insights into the pathogenesis of this disease.

2.
Front Genet ; 10: 174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915103

RESUMO

Atopic dermatitis (AD) is a common inflammatory skin disease with high heritability. Two susceptibility loci have been confirmed in our previous AD genome-wide association study (GWAS). To look for additional genetic factors in Chinese Han ethnicity, we performed a large-scale GWAS follow-up study. Forty-nine top single nucleotide polymorphisms (SNPs) that had never been reported previously were genotyped using Sequenom Massarray system in an independent cohort, which consist of northern Chinese (1634 cases and 1263 controls) and southern Chinese (2985 cases and 9526 controls). Association analyses were performed using PLINK 2 software. Three SNPs in northern and ten SNPs in southern were found exhibiting association evidence with AD (P < 0.05). Finally, SNP rs224108 on 10q21.2 showed high significance for AD in joint analysis of GWAS and replication study (P meta = 4.55 × 10-9, OR = 1.21), and was confirmed as an independent genetic marker by Linkage disequilibrium calculation and conditional logistic regression analysis. Bioinformatics analysis strongly suggested that rs224108 may have the potential to alter the target gene expression through non-coding epigenetic regulation effects. Meanwhile, SNP rs11150780 on 17q25.3 was also found suggestive association with AD (P meta = 7.64 × 10-7, OR = 1.18). Our findings confirmed a novel susceptibility signal on 10q21.2 for AD in Chinese Han population and advanced the understanding of the genetic contribution to AD.

3.
Clin Epigenetics ; 10(1): 160, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587242

RESUMO

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.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigenômica/métodos , Psoríase/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
J Investig Dermatol Symp Proc ; 19(2): S79-S80, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30471757

RESUMO

Major histocompatibility complex (MHC), also known as human leukocyte antigen (HLA) in humans, is one of the most genetically diverse regions in the genome of various species. The human MHC contains about 400 genes in a ∼7.6-Mb span located on the short arm of the chromosomal region 6p21.3. According to the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/) in HLA region, more than 500 associations have been identified for about 200 traits or phenotypes, including primary immune deficiencies, autoimmune diseases, susceptibility to infections, malignancies, and psychiatric conditions (Welter et al., 2014). For example, multiple sclerosis is associated with HLA-DRB1∗1501 (Handunnetthi et al., 2010); the control of HIV viral load is associated with variants near HLA-C (Kulpa and Collins, 2011). Some acute drug reactions are associated with specific HLA alleles. Carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis have been strongly associated with HLA-B*1502 in Han Chinese population and HLA-A*3101 in European populations (Chung et al., 2004; McCormack et al., 2011). The HLA-B*13:01 is associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy (Zhang et al., 2013).

5.
ACS Med Chem Lett ; 9(7): 719-724, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034607

RESUMO

The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/ß/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

6.
J Dermatol Sci ; 91(3): 285-291, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29914851

RESUMO

BACKGROUND: Recent studies have revealed that DNA methylation (DNAm) could modulate gene expression in psoriasis (Ps). However, the relationship between whole-genome DNAm and gene expression in Ps has not been studied yet. OBJECTIVES: To better characterize the relationship between DNAm and gene expression, and to identify biological pathways triggered by changes in methylation involved in the pathogenesis of Ps. METHODS: Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were analysed by comparing 20 involved psoriatic (PP) skin, 20 uninvolved psoriatic (PN) skin and 20 normal (NN) skin biopsies. DEGs in negative correlation with the methylation were entered into further Gene Ontology (GO) and pathway analysis by clusterProfiler package in R program. RESULTS: A total of 290 genes with reverse correlation overlapped in PP vs PN and PP vs NN comparisons. GO categories of reversely-associated genes mainly enriched in T cell activation, type I interferon signaling pathway and defense response to other organism. Pathway analysis revealed superior NOD-like receptor signaling pathway and Measles enriched in the differentially up-regulated transcripts and regulation of lipolysis in adipocytes in the down-regulated transcripts. CONCLUSIONS: Our results provided a comprehensive correlation analysis of transcriptome and methylome in Ps. Increased innate immunity and decreased lipid biosynthesis play important roles in the development of psoriatic skin. This integrated analysis shed light on novel insights into the pathogenic mechanisms involved in Ps.


Assuntos
Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica/métodos , Psoríase/genética , Transcriptoma , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Biologia Computacional , Bases de Dados Genéticas , Redes Reguladoras de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Lipogênese/genética , Fenótipo , Psoríase/etnologia , Psoríase/imunologia , Psoríase/metabolismo , Pele/imunologia , Pele/metabolismo
7.
PLoS One ; 13(6): e0199322, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902262

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0196635.].

8.
J Invest Dermatol ; 138(11): 2307-2314, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29857070

RESUMO

To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10-8, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.


Assuntos
Genótipo , Complexo Principal de Histocompatibilidade/genética , Pênfigo/genética , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Autoimunidade/genética , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cadeias alfa de HLA-DR/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Risco
9.
Cell Immunol ; 331: 16-21, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29748001

RESUMO

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.


Assuntos
Interleucina-17/imunologia , Subunidade p50 de NF-kappa B/imunologia , Psoríase/imunologia , Células Th1/imunologia , Adulto , Animais , Linhagem Celular , Células Cultivadas , Citocinas/sangue , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Imiquimode , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Psoríase/induzido quimicamente , Psoríase/metabolismo , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células Th1/metabolismo , Adulto Jovem
10.
Hum Genomics ; 12(1): 27, 2018 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-29784039

RESUMO

BACKGROUND: Mutations in keratin proteins have been vastly associated with a wide array of genodermatoses; however, mutations of keratins in psoriasis have not been fully investigated. The main aim of the current research was to identify the mutation in K14, K10, K16, and K17 genes in two stages of psoriasis patients. METHODS: Ninety-six psoriatic skin biopsies were collected. mRNA transcript of K14, K10, K16, and K17 was prepared, amplified, and sequenced. Sanger sequences of all keratins were further validated for mutational analysis using Mutation Surveyor and Alamut Visual. Then, in silico analysis of protein stability and protein and gene expression of all keratins was performed and validated. RESULTS: Out of 44 mutations, about 75% of keratins are highly pathogenic and deleterious. Remaining 25% mutations are less pathogenic and tolerated in nature. In these 33 deleterious mutations were immensely found to decrease keratin protein stability. We also found a correlation between keratin and Psoriasis Area and Severity Index score which added that alteration in keratin gene in skin causes severity of psoriasis. CONCLUSIONS: We strongly concluded that acanthosis and abnormal terminal differentiation was mainly due to the mutation in epidermal keratins. In turn, disease severity and relapsing of psoriasis are mainly due to the mutation of hyperproliferative keratins. These novel keratin mutations in psoriatic epidermis might be one of the causative factors for psoriasis.


Assuntos
Queratinas Tipo I/genética , Queratinas/genética , Mutação/genética , Psoríase/genética , Acantose Nigricans/genética , Acantose Nigricans/fisiopatologia , Adolescente , Adulto , Idoso , Biópsia , Diferenciação Celular , Proliferação de Células/genética , Análise Mutacional de DNA , Epiderme/metabolismo , Epiderme/fisiopatologia , Feminino , Humanos , Queratinas/classificação , Masculino , Pessoa de Meia-Idade , Estabilidade Proteica , Psoríase/patologia , Índice de Gravidade de Doença , Pele/metabolismo , Pele/patologia , Adulto Jovem
11.
PLoS One ; 13(5): e0196635, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29715312

RESUMO

Psoriasis is a common inflammatory skin disease, with considerable genetic contribution. Genome-wide association studies have successfully identified a number of genomic regions for the risk of psoriasis. However, it is challenging to pinpoint the functional causal variants and then further decipher the genetic mechanisms underlying each region. In order to prioritize potential functional causal variants within psoriasis susceptibility regions, we integrated the genetic association findings and functional genomic data publicly available, i.e. histone modifications in relevant immune cells. We characterized a pervasive enrichment pattern of psoriasis variants in five core histone marks across immune cells/tissues. We discovered that genetic alleles within psoriasis association regions might influence gene expression levels through significantly affecting the binding affinities of 17 transcription factors. We established a catalog of 654 potential functional causal variants for psoriasis and suggested that they significantly overlapped with causal variants for autoimmune diseases. We identified potential causal variant rs79824801 overlay with the peaks of five histone marks in primary CD4+ T cells. Its alternative allele affected the binding affinity of transcription factor IKZF1. This study highlights the complex genetic architecture and complicated mechanisms for psoriasis. The findings will inform the functional experiment design for psoriasis.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Psoríase/genética , Alelos , Doenças Autoimunes/genética , Linhagem Celular , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fatores de Transcrição/genética
12.
J Dermatol ; 45(7): 867-870, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29740858

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non-pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ2 -tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.


Assuntos
Deficiência Intelectual/genética , Convulsões/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Encéfalo/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Eletroencefalografia , Éxons/genética , Feminino , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Mutação , Fenótipo , Convulsões/diagnóstico , Pele/patologia , Tomografia Computadorizada por Raios X , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
13.
Front Med ; 12(6): 717-725, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29623515

RESUMO

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


Assuntos
Metilação de DNA , Psoríase/classificação , Psoríase/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , China , Proteínas Ricas em Prolina do Estrato Córneo/genética , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Humanos , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem , beta-Defensinas/genética
14.
Bioorg Med Chem Lett ; 28(7): 1257-1261, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29534926

RESUMO

A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
16.
Exp Cell Res ; 365(1): 138-144, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29501569

RESUMO

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.


Assuntos
Linfócitos B/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cromonas/farmacologia , Humanos , Imunoglobulina G/metabolismo , Morfolinas/farmacologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sincalida/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Cancer Res ; 78(11): 3087-3097, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29572226

RESUMO

Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new noncoding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10-8) and CNFN (P = 3.77 × 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087-97. ©2018 AACR.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Exoma/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
18.
Ann Hum Genet ; 82(4): 200-205, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29297929

RESUMO

The polymorphism of PRKCB has been proven to be associated with systemic lupus erythematosus (SLE) in our previous study. We aimed to investigate the relationship between expression of PRKCB mRNA and the Disease Activity Index (SLEDAI) and manifestations of SLE. Quantitative reverse transcription polymerase chain reaction (RT-PCR) was applied to examine the expression of PRKCB mRNA in peripheral blood mononuclear cells of 60 patients with SLE and 62 controls. The Sequenom MassArray System was used to detect genotype SNP rs16972959. The expression levels of PRKCB mRNA in SLE cases were significantly increased compared with those in healthy controls (P < 0.001). In addition, PRKCB mRNA expression levels were negatively correlated with the SLEDAI (P < 0.05, r = -0.322), with lower mRNA expression levels of PRKCB in patients found with higher SLEDAI, presence of a new rash (P < 0.01), and proteinuria (P < 0.05). No association evidence was observed between the genotype of the variant rs16972959 and PRKCB mRNA expression levels; however, SNP rs16972959 was found to be an expression quantitative trait loci for PRKCB with the SLE risk allele correlated with increased expression in naïve monocytes (PFDR  = 9.12 × 10-13 ) and stimulated monocytes (9.24 × 10-6  > PFDR  > 2.75 × 10-17 ). On the other hand, SNP rs16972959 of PRKCB was found to have suggestive significant associations with vasculitis (P = 0.00718) of SLE. These results indicated that expression of PRKCB mRNA may be correlated with the pathogenesis of SLE; however, more investigation is still needed.


Assuntos
Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Proteína Quinase C beta/genética , Adulto , Alelos , Estudos de Casos e Controles , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteína Quinase C beta/metabolismo , RNA Mensageiro/genética , Adulto Jovem
19.
Gene ; 648: 76-81, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29355683

RESUMO

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-DQß1 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 ß2 domain of the HLA-DQß1 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.


Assuntos
Predisposição Genética para Doença/genética , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , Vitiligo/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Mapeamento Cromossômico/métodos , Frequência do Gene , Predisposição Genética para Doença/etnologia , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Fatores de Risco , Vitiligo/etnologia
20.
Ann Rheum Dis ; 77(3): 417, 2018 03.
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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Exoma , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Reação em Cadeia da Polimerase em Tempo Real
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