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1.
Cancer Epidemiol ; 73: 101972, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34216957

RESUMO

BACKGROUND: Aberrant Wnt/beta-catenin pathway activation is implicated in Multiple Myeloma (MM) development, but little is known if genetic variants within this pathway contribute to MM susceptibility. METHODS: We performed a discovery candidate pathway analysis in 269 non-Hispanic white MM cases and 272 controls focusing on 171 variants selected from 26 core genes within the Wnt/beta-catenin pathway. Significant candidate variants (P < 0.05) were selected for validation in internal and external non-Hispanic white populations totaling 818 cases and 1209 controls. We also examined significant variants in non-Hispanic black and Hispanic case/control study populations to identify potential differences by race/ethnicity. Possible biological functions of candidate variants were predicted in silico. RESULTS: Seven variants were significantly associated with MM risk in non-Hispanic whites in the discovery population, of which LRP6:rs7966410 (OR: 0.57; 95 % CI: 0.38-0.88; P = 9.90 × 10-3) and LRP6:rs7956971 (OR: 0.64; 95 % CI: 0.44-0.95; P = 0.027) remained significant in the internal and external populations. CSNK1D:rs9901910 replicated among all three racial/ethnic groups, with 2-6 fold increased risk of MM (OR: 2.40; 95 % CI: 1.67-3.45; P = 2.43 × 10-6 - non-Hispanic white; OR: 6.42; 95 % CI: 2.47-16.7; P = 3.14 × 10-4 - non-Hispanic black; OR: 4.31; 95 % CI: 1.83-10.1; P = 8.10 × 10-4 - Hispanic). BTRC:rs7916830 was associated with a significant 37 % and 24 % reduced risk of MM in the non-Hispanic white (95 % CI: 0.49-0.82; P = 5.60 × 10-4) and non-Hispanic Black (95 % CI: 0.60-0.97; P = 0.028) population, respectively. In silico tools predicted that these loci altered function through via gene regulation. CONCLUSION: We identified several variants within the Wnt/beta-catenin pathway associated with MM susceptibility. Findings of this study highlight the potential genetic role of Wnt/beta-catenin signaling in MM etiology among a diverse patient population.


Assuntos
Mieloma Múltiplo , Via de Sinalização Wnt , beta Catenina , Afro-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Predisposição Genética para Doença/etnologia , Hispano-Americanos/genética , Hispano-Americanos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/etnologia , Mieloma Múltiplo/genética , Via de Sinalização Wnt/genética , beta Catenina/genética
2.
Commun Biol ; 4(1): 864, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294844

RESUMO

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Transtornos de Enxaqueca/genética , Adulto , Afro-Americanos/genética , Idoso , Americanos Asiáticos/genética , Mapeamento Cromossômico , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etnologia , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
3.
Medicine (Baltimore) ; 100(15): e24523, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847607

RESUMO

BACKGROUND: Infertility affects childbearing age couples all over the world. One of the important reasons for infertility is genetic factors. Our study evaluated the association between methylenetetrahydrofolate reductase (MTHFR) and azoospermia. METHODS: Multiple databases like MEDLINE, EMBASE, Cochrane library, and China journal full-text database were used to search for relevant studies, and full-text articles involved in the evaluation of MTHFR and azoospermia. The results were evaluated using STATA 12.0. Heterogeneity analysis, sensitivity analysis, and bias analysis were also performed on the data. RESULTS: Thirteen related studies eventually met the inclusion criteria. Significant association between C677T polymorphism and azoospermia (relative risk [RR] = 0.94 [0.90, 0.99], I2 = 60.9%, P = .002), and between A1298C polymorphism and azoospermia (RR = 0.98 [0.94, 1.02], I2 = 56.3%, P = .011) was observed. Meanwhile, in subgroup analysis, Caucasians had higher risk than Mongolians in association between MTHFR and azoospermia. CONCLUSION: There was association between MTHFR polymorphism and azoospermia. Caucasian populations had higher risk than Mongolian populations in association between MTHFR and azoospermia.


Assuntos
Azoospermia/genética , Predisposição Genética para Doença/etnologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Nat Rev Rheumatol ; 17(6): 363-374, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33850309

RESUMO

Historically, rheumatic diseases have not received much attention in Africa, particularly in sub-Saharan Africa, possibly owing to a focus on the overwhelming incidence of infectious diseases and the decreased life span of the general population in this region. Global attention and support, together with better health policies and planning, have improved outcomes for many infectious diseases; thus, increasing attention is being turned to chronic non-communicable diseases. Rheumatic diseases were previously considered to be rare among Africans but there is now a growing interest in these conditions, particularly as the number of rheumatologists on the continent increases. This interest has resulted in a growing number of publications from Africa on the more commonly encountered rheumatic diseases, as well as case reports of rare diseases. Despite the limited amount of available data, some aspects of the epidemiology, genetics and clinical and laboratory features of rheumatic diseases in African populations are known, as is some detail on the use of therapeutics. Similarities and differences in these conditions can be seen across the multi-ethnic and genetically diverse African continent, and it is hoped that increased awareness of rheumatic diseases in Africa will lead to earlier diagnosis and better outcomes for patients.


Assuntos
Predisposição Genética para Doença/epidemiologia , Publicações/estatística & dados numéricos , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/epidemiologia , Reumatologistas/estatística & dados numéricos , Adulto , África ao Sul do Saara/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Conscientização , Comorbidade , Gerenciamento Clínico , Meio Ambiente , Feminino , Predisposição Genética para Doença/etnologia , Política de Saúde , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Publicações/provisão & distribuição , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/genética , Fatores de Risco
5.
Nutrients ; 13(3)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806559

RESUMO

Vitamin D plays an important role in bone metabolism and is important for the prevention of multifactorial pathologies, including osteoporosis (OP). The biological action of vitamin is realized through its receptor, which is coded by the VDR gene. VDR gene polymorphism can influence individual predisposition to OP and response to vitamin D supplementation. The aim of this work was to reveal the effects of VDR gene ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570, and Cdx2 rs11568820 variants on bone mineral density (BMD), 25-hydroxyvitamin D level, and OP risk in Belarusian women. METHODS: The case group included 355 women with postmenopausal OP, and the control group comprised 247 women who met the inclusion criteria. TaqMan genotyping assay was used to determine VDR gene variants. RESULTS: Rs7975232 A/A, rs1544410 T/T, and rs731236 G/G single variants and their A-T-G haplotype showed a significant association with increased OP risk (for A-T-G, OR = 1.8, p = 0.0001) and decreased BMD (A-T-G, -0.09 g/cm2, p = 0.0001). The rs11568820 A-allele showed a protective effect on BMD (+0.22 g/cm2, p = 0.027). A significant dose effect with 25(OH)D was found for rs1544410, rs731236, and rs11568820 genotypes. Rs731236 A/A was associated with the 25(OH)D deficiency state. CONCLUSION: Our novel data on the relationship between VDR gene variants and BMD, 25(OH)D level, and OP risk highlights the importance of genetic markers for personalized medicine strategy.


Assuntos
Densidade Óssea/genética , Grupo com Ancestrais do Continente Europeu/genética , Estado Nutricional/genética , Pós-Menopausa/genética , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Alelos , Estudos de Casos e Controles , Estudos Transversais , Grupo com Ancestrais do Continente Europeu/etnologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/etnologia , Osteoporose Pós-Menopausa/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/etnologia , República de Belarus , Vitamina D/sangue
6.
Medicine (Baltimore) ; 100(11): e24818, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725949

RESUMO

ABSTRACT: Osteosarcoma is a malignant tumor that develops from a mesenchymal cell line and is caused by gene-environment interactions. This study aimed to explore whether TIMP2/TIMP3 polymorphisms influenced the osteosarcoma risk.The expression of the TIMP2 and TIMP3 genes in osteosarcoma histiocytes was analyzed by immunohistochemistry. In this case-control study, which includes samples from 499 patients and 500 healthy controls, 10 single-nucleotide polymorphisms (SNPs) in TIMP2 and TIMP3 were selected. Furthermore, we used the Agena MassARRAY platform for genotyping. The statistical analysis was performed using χ2 test/Fisher exact test, and logistic regression analysis.The immunohistochemistry results showed that the expression of TIMP2 is obvious higher in osteosarcoma histiocytes than in the normal histiocytes. The association study indicated that the allele of rs2277698 and rs4789936 were protective SNPs reducing the risk of osteosarcoma (odds ratios  > 1, P < .05) by the χ2 test. In the genetic model, logistic regression analyses revealed that the rs2277698 and rs4789936 were associated with decreasing the risk of osteosarcoma under the codominant model, dominant model, and log-additive model. Stratification analysis revealed that 2 SNPs (rs2277698 and rs4789936) were significantly associated with a reduced risk of osteosarcoma in allele and genetic model after stratification by gender or age (P < .05). In addition, the haplotype "Trs2277698Crs2009169Crs7342880" of TIMP2 was associated with decreasing the osteosarcoma risk. The "Ars9609634Trs11547635" of TIMP3 was associated with reducing the osteosarcoma risk.This finding shed new light on the high expression of TIMP2 polymorphisms may contribute to decreasing the osteosarcoma risk in Zhejiang populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Ósseas/genética , Osteossarcoma/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Adolescente , Idoso , Alelos , Neoplasias Ósseas/etnologia , Estudos de Casos e Controles , China/etnologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Osteossarcoma/etnologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
7.
Medicine (Baltimore) ; 100(11): e25113, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725991

RESUMO

BACKGROUND: Recent studies have reported that lncRNA (long noncoding RNAs) antisense non-coding RNA in the INK4 locus (ANRIL) plays important roles in the development of atherosclerosis through regulating cell apoptosis, proliferation, and adhesion. GWAS (genome-wide association studies) identified common genetic variants within ANRIL could confer risk of ischemic stroke (IS) in southern Sweden. METHODS: We performed a case-control study, including 567 IS patients and 552 healthy controls from unrelated northern Chinese Han population, aiming to explore the association between lncRNA ANRIL rs2383207, rs4977574 polymorphisms and the risk of IS. Subsequently we implemented a meta-analysis to further assess the relationship of these variants and the disease. RESULTS: In our case-control study, no significant associations were observed in all models between above 2 polymorphisms and IS. Next in our subgroup analysis, we detected significant association between GA genotype of rs4977574 and the increased risk of LAA-IS (large-artery atherosclerotic ischemic stroke), similar elevated risk also appeared in the GG + GA genotype under the dominant model (P = .048, OR = 1.385, 95% CIs 1.002-1.914; P = .040, OR = 1.378, 95% CIs 1.015-1.872, respectively). As for rs2383207, negative results were obtained under all models and subgroups. Our meta-analysis showed a significant association between rs4977574 polymorphism and IS risk in allele model (G vs A P = .002, OR = 1.137, 95% CIs 1.048-1.234); with respect to rs2383207 polymorphism, no significant association between that and the risk of IS was detected under the dominant model (GA + AA vs GG, P = .061, OR = 0.923, 95% CIs 0.849-1.004), or recessive model (AA vs GA + GG, P = .656, OR = 0.972, 95% CIs 0.858-1.101), or allele model (A vs G, P = .326, OR = 0.952, 95% CIs 0.863-1.050). Likewise, no significant association between rs2383207 and IS was found in different stoke subtypes (P > .05). CONCLUSIONS: Our findings indicated G allele of lncRNA ANRIL rs4977574 could increase the risk of IS, and the variant may be associated with susceptibility to LAA-IS in Chinese Han population.


Assuntos
Predisposição Genética para Doença/genética , AVC Isquêmico/genética , Polimorfismo Genético/genética , RNA Longo não Codificante/sangue , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/epidemiologia , Aterosclerose/etnologia , Aterosclerose/genética , Estudos de Casos e Controles , China/epidemiologia , China/etnologia , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/etnologia , Doença da Artéria Coronariana/genética , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , AVC Isquêmico/epidemiologia , AVC Isquêmico/etnologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Clin Rheumatol ; 40(8): 3095-3103, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33575923

RESUMO

INTRODUCTION: Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease that disrupts numerous immunity mechanisms with the potential to exert damage to any organ or tissue. Its etiology remains uncertain; however, genetic and environmental factors that differ between populations strongly influence its development. Among the physiopathogenic factors, the genetic ones predominate, notably the major histocompatibility complex (MHC) loci. A high degree of ethnical admixture makes Mexican Mestizos a thoroughly genetically heterogeneous population. Therefore, this study aimed to identify the MHC polymorphisms associated with SLE development in Mexican Mestizos from Southern Mexico and compare them with patients from Mexico City. METHOD: A transversal study in SLE patients from Tapachula, Chiapas, was conducted. DNA typing of human leukocyte antigens (HLA) classes I and II was performed using single specific primers (SSP). Admixture analysis was performed using the population genetics LEADMIX software. RESULTS: The frequencies of HLA-DRB1*16 and HLA-DQB1*05 were found to have a tendency towards increase in SLE patients, compared to ethnically matched healthy controls. The allele HLA-DRB1*03 seemed to be less associated with SLE in this group of Mexican Mestizos, opposed to other more Caucasian populations. Admixture analysis showed a higher Mayan genetic component in these patients from Chiapas. CONCLUSIONS: The genetic susceptibility for SLE differed in two populations of Mexican Mestizos with dissimilar ethnic ancestries. Autochthonous Amerindian alleles, and not the more widely known Caucasian alleles, might be associated with the susceptibility to SLE in Mexican Mestizos from Tapachula, Chiapas. Key Points • Autochthonous Amerindian alleles, such as HLA-DRB1*16, had a tendency to be increased in SLE patients, compared to healthy controls. • SLE susceptibility alleles vary considerably among regions in Mexico, according to the distribution of the indigenous groups. • Ethnic admixture is a key determinant in the genetic susceptibility of SLE.


Assuntos
Predisposição Genética para Doença , Cadeias HLA-DRB1 , Lúpus Eritematoso Sistêmico , Alelos , Frequência do Gene , Predisposição Genética para Doença/etnologia , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Complexo Principal de Histocompatibilidade , México
9.
Nat Commun ; 12(1): 772, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536424

RESUMO

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.


Assuntos
Heterogeneidade Genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/etnologia
10.
Mycoses ; 64(4): 405-411, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33320373

RESUMO

BACKGROUND: For Chinese Han populations, cryptococcosis are more likely to occur in HIV-uninfected patients instead of HIV-infected patients compared with other countries and regions, implying that there may be genetic predisposing factors for cryptococcosis in the Chinese Han populations. However, the retail mechanism has not been clarified. OBJECTIVES: We aimed to conduct an association analysis between the single nucleotide polymorphisms (SNPs) of pattern recognition receptors (PRR) genes and the susceptibility to cryptococcosis in HIV-uninfected Chinese patients, which may provide new genetic predisposing factors for early-risk prediction of disease, individualised treatment and prognosis monitoring. PATIENTS/METHODS: Using the SNaPshot SNP typing technique, eight SNPs of PRR genes (Dectin-2, Dectin-1, PTX3, CXCL8, IL12B, IFIH1, TLR1 and CD209) were typed on 97 HIV-uninfected cryptococcosis patients and 120 healthy controls who admitted to West China Hospital, Sichuan University, China, from 1 March 2018 to 30 December 2018. The results were analysed by the SHEsis software and SPSS 20.0 software. RESULTS: It was found that that PTX3 rs2305619 polymorphism was associated with cryptococcosis in HIV-uninfected patients. Compared with the GG genotype, AA genotype increased the risk of cryptococcosis in HIV-uninfected patients (p = .015, OR, 2.579; 95% CI, 1.202-5.535). In the immunocompetent patients, the AA genotype had a higher risk (p = .002, OR, 4.399; 95% CI, 1.745-11.088). Further verification found that the plasma PTX3 level of the AA genotype was significantly higher than the GA or GG genotype (60.28 ± 16.12 vs 7.32 ± 0.79, p < .001). CONCLUSIONS: PTX3 rs2305619 polymorphism was associated with cryptococcosis in HIV-uninfected Chinese patients. The AA genotype increased the risk of cryptococcosis, and its plasma PTX3 level was significantly higher than that of GA or GG genotype.


Assuntos
Proteína C-Reativa/genética , Criptococose/genética , Predisposição Genética para Doença/etnologia , Genótipo , Polimorfismo de Nucleotídeo Único , Componente Amiloide P Sérico/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Criptococose/etnologia , Feminino , Estudos de Associação Genética , Infecções por HIV , Humanos , Masculino , Pessoa de Meia-Idade
11.
Ann Rheum Dis ; 80(5): 558-565, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33310728

RESUMO

OBJECTIVES: Nearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations. METHODS: Genome-wide RA association summary statistics in three large case-control collections consisting of 311 292 individuals of Korean, Japanese and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritise causal variants and genes, RA variant-implicating features (tissues, pathways and transcription factors) and potentially repurposable drugs for RA treatment. RESULTS: We identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the single-nucleotide polymorphism-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-human leukocyte antigens (HLA) susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription-activation histone marks that simultaneously highlighted the importance of CD4+ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications. CONCLUSION: Our findings provide useful insights regarding RA genetic aetiology and variant-driven RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Japão/etnologia , Polimorfismo de Nucleotídeo Único , República da Coreia/etnologia
12.
Medicine (Baltimore) ; 99(50): e23652, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327349

RESUMO

BACKGROUND: Polymorphisms in the cytochrome P450 2C19 (CYP2C19) gene have been reported to be associated with coronary heart disease (CHD), but the results were not consistently analyzed among different patient groups. To derive a more precise estimation of these associations, we will conduct a meta-analysis to investigate the polymorphisms of CYP2C19 in all published studies. METHODS: Electronic databases (Google Scholar, ISI Web of Science, Pubmed, Embase, China National Knowledge Infrastructure, Wanfang, and China Biological Medicine) will be used to search clinical case-control or cohort studies about CYP2C19 polymorphism and CHD published until November 2020. Two reviewers will independently select the study, extract the data, and evaluate the quality of the study. Odds ratios with 95% confidence interval will be used to evaluate the strength of the association between the CYP2C19 polymorphism and CHD susceptibility under 4 genetic models. Subgroup analysis will be conducted by different ethnicity and genotyping method. Sensitivity analysis will be performed via sequentially omitting each of the included studies 1 at a time. Begg funnel plots and Egger test will be used to examine the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0. RESULTS: This study will provide a better understanding of the association between CYP2C19 polymorphisms and coronary heart disease risk. CONCLUSION: The publication of this protocol will minimize the possibility of bias due to post hoc changes to the analysis protocol, thus helping to obtain reliable evidence. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/R7U93.


Assuntos
Doença das Coronárias/genética , Citocromo P-450 CYP2C19/genética , Predisposição Genética para Doença/genética , Doença das Coronárias/etnologia , Grupos Étnicos , Predisposição Genética para Doença/etnologia , Técnicas de Genotipagem , Humanos , Metanálise como Assunto , Razão de Chances , Polimorfismo Genético , Reprodutibilidade dos Testes , Projetos de Pesquisa , Fatores de Risco , Revisões Sistemáticas como Assunto/métodos
13.
Viruses ; 12(11)2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138079

RESUMO

(1) Background: The influenza A/H1N1 pdm09 virus rapidly spread throughout the world. Despite the inflammatory and virus-degradation pathways described in the pathogenesis of influenza A virus (IAV) infection, little is known about the role of the single nucleotide polymorphisms (SNPs) in the genes involved in the processing and antigenic presentation-related mechanisms. (2) Methods: In this case-control study, we evaluated 17 SNPs in five genes (TAP1, TAP2, TAPBP, PSMB8, and PSMB9). One hundred and twenty-eight patients with influenza A/H1N1 infection (INF-P) and 111 healthy contacts (HC) were included; all of them are Mexican mestizo. (3) Results: In allele and genotype comparison, the rs241433/C allele (TAP2), as well as AG haplotype (rs3763365 and rs4148882), are associated with reduced risk for influenza A/H1N1 infection (p < 0.05). On the other hand, the rs2071888G allele (TAPBP) and GG haplotype (rs3763365 and rs9276810) are associated with a higher risk for influenza A/H1N1 infection. In addition, after adjustment for covariates, the association to a reduced risk for influenza A/H1N1 infection remains with rs241433/C allele (p < 0.0001, OR = 0.24, 95% CI = 0.13-0.43), and the association with TAPBP is also maintained with the G allele (p = 0.0095, OR = 1.89, 95% CI = 1.17-3.06) and GG genotype models (p < 0.05, OR = 2.18, 95% CI = 1.27-3.74). (4) Conclusion: The rs241433/C allele and AC genotype (TAP2) and the AG haplotype are associated with a reduced risk for influenza A/H1N1 infection. In addition, the rs2071888/G allele and GG genotype (TAPBP) and the GG haplotype are associated with a higher risk for developing influenza A/H1N1 infection in a Mexican mestizo population.


Assuntos
Apresentação do Antígeno/genética , Predisposição Genética para Doença/etnologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/epidemiologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Haplótipos , Humanos , Influenza Humana/etnologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Medicine (Baltimore) ; 99(45): e23068, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157966

RESUMO

BACKGROUND: Generalized pustular psoriasis (GPP) is a systemic inflammatory disease with poor outcomes, and several studies have suggested that the mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to GPP, where the polymorphism c.115+6T>C is reported to be the most common mutation of IL36RN. This study was performed to clarify and comprehensively evaluate the relationship between IL36RN gene polymorphism and the susceptibility of GPP subtypes. METHODS: To conduct a thorough literature review, studies were obtained using databases such as Pubmed, EMBASE, Cochrane, China National Knowledge Infrastructure, and the Wanfang database. Only studies published up to December 2019 were included. The quality of the research studies was estimated using the Newcastle-Ottawa scale. The total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were pooled and analysed using STATA 14. The publication bias was evaluated through the Egger test, performed using the aforementioned software. Five common gene models were built and analysed to assess the association between the polymorphism c.115+6T>C and subtypes of GPP. RESULTS: A total of 10 studies were selected, including 683 cases of GPP patients. Meta-analyses showed that there was a significant statistical correlation of IL36RN mutation between GPP with or without psoriasis vulgaris (OR = 3.82, 95%CI 2.63-5.56) and between adult GPP and paediatric GPP (OR = 0.42, 95%CI 0.23-0.77). No obvious discrepancy between European patients (OR = 4.03, 95%CI 2.23-7.26) and Asian patients was found. The gene models showed clear associations between the polymorphism c.115+6T>C and GPP through the dominant model (CC+ TC vs TT, OR 2.74, 95%CI 2.06-3.64), recessive model (CC vs CT + TT, OR 4.33, 95%CI 2.84-6.60), homozygote model (CC vs TT, OR 4.37, 95%CI 2.88-6.62), heterozygote model (CT vs TT, OR 2.26, 95%CI 1.32-3.85) and allelic model (C vs T, OR 3.35, 95%CI 2.63-4.27). CONCLUSION: The IL36RN mutation is strongly related to GPP without psoriasis vulgaris and the early onset of GPP. Furthermore, the single-nucleotide polymorphism c.115+6T>C of the IL36RN gene plays a significant role in GPP vulnerability, especially in homozygous mutation. GPP could be a different inflammatory disease, independent of psoriasis.


Assuntos
Predisposição Genética para Doença/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único/genética , Psoríase/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Gerenciamento de Dados , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/etnologia , Heterozigoto , Homozigoto , Humanos , Mutação/genética , Psoríase/microbiologia , Psoríase/patologia , Adulto Jovem
15.
BMC Pregnancy Childbirth ; 20(1): 714, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228578

RESUMO

BACKGROUND: Vitamin D deficiency (VDD) has been related to vitamin D binding protein (GC) gene polymorphism, demographics and lifestyle factors in different populations. However, previous studies only focused on demographic and lifestyle factors or genetic factors alone. Therefore, this cross-sectional study aimed to assess the association between GC gene polymorphism, demographics and lifestyle factors with VDD among Malaysian pregnant women. METHOD: Information on demographic characteristics, dietary vitamin D intake from supplement and food, time spent outdoors, skin type and clothing were collected using a questionnaire. Plasma total 25-hydroxyvitamin D (25OHD) levels were measured using an Ultra-High-Performance Liquid Chromatography (UHPLC). Maternal GC single nucleotide polymorphisms (SNPs) (rs4588 and rs7041) were determined using restriction fragment length polymorphism (RFLP) technique. RESULTS: Results showed that 50.2% of pregnant women were vitamin D deficient (25OHD < 30 nmol/L). VDD (25OHD < 30 nmol/L) was significantly associated with age, veiled clothing, maternal vitamin D intakes from both food and supplements, and GC rs7041(and GC diplotypes). In contrast to previous studies that reported for non-pregnant population, a significant positive association was found between CC genotype for SNP GC rs7041, GC 1s-1s and GC If-2 with risk of VDD (25OHD < 30 nmol/L). CONCLUSIONS: The high prevalence of maternal VDD found in this study suggests the need for urgent development and implementation of vitamin D supplementation or fortification strategies to reduce VDD among pregnant women. The discrepancy in the association between GC rs7041 gene polymorphism and VDD reflects the variation in the factors associated with VDD in pregnancy compared to non-pregnant state.


Assuntos
Deficiência de Vitamina D/etnologia , Deficiência de Vitamina D/genética , Proteína de Ligação a Vitamina D/genética , Vitamina D/análogos & derivados , Adulto , Alelos , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Grupos Étnicos/genética , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Estilo de Vida , Malásia/epidemiologia , Polimorfismo de Nucleotídeo Único , Gravidez , Vitamina D/sangue , Deficiência de Vitamina D/sangue
16.
Medicine (Baltimore) ; 99(46): e23164, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181690

RESUMO

BACKGROUND: Recently, many studies have been conducted to investigate the relationship between the A46G polymorphism in the ß2-adrenergic receptor (ADRB2) gene and essential hypertension risk in the Chinese population. However, the results of previous studies were conflicting. OBJECTIVES: The present study aimed to investigate the association between the ADRB2 A46G polymorphism and the risk of essential hypertension in the Chinese population. METHODS: We performed a systematic search of possible relevant studies on PubMed, Embase, Ovid, Web of Science, China National Knowledge Infrastructure, Wanfang, and China Biology Medicine disc databases up to January 3, 2020. Two authors independently extracted information from included articles and assessed the quality of each study by the use of the Newcastle-Ottawa Scale. According to the extent of interstudy heterogeneity, either a random-effect model or a fixed-effect model was used to calculate the combined odds ratio (OR) and 95% confidence interval (CI). RESULTS: Finally, 16 studies containing 3390 cases and 2528 controls were included in our meta-analysis. Significant associations were found between the ADRB2 A46G polymorphism and essential hypertension risk in the Chinese population under four genetic models: allele genetic model (OR: 1.14, 95% CI: 1.06-1.23, P = .001, Pheterogeneity = .09), homozygote genetic model (OR: 1.29, 95% CI: 1.11-1.51, P = .001, Pheterogeneity = .25), dominant genetic model (OR: 1.17, 95% CI: 1.05-1.32, P = .005, Pheterogeneity = .04), and recessive genetic model (OR: 1.21, 95% CI: 1.05-1.38, P = .007, Pheterogeneity = .72). CONCLUSION: The ADRB2 A46G polymorphism may increase the risk of essential hypertension in the Chinese population.


Assuntos
Hipertensão Essencial , Receptores Adrenérgicos beta 2/genética , Grupo com Ancestrais do Continente Asiático/genética , Hipertensão Essencial/etnologia , Hipertensão Essencial/genética , Predisposição Genética para Doença/etnologia , Humanos , Polimorfismo de Nucleotídeo Único
17.
BMC Med Genet ; 21(1): 199, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036557

RESUMO

BACKGROUND: This case-control study aims to examine the association between the Interleukin-6 (IL-6) rs12700386 polymorphism and the increased risk of developing osteoarthritis (OA) in the knee in the Chinese Han population. METHODS: We extracted DNA from 763 subjects (352 OA patients and 411 healthy controls). The relative expression levels of IL-6 in blood samples of patients with knee OA was determined by quantitative reverse transcription PCR (qRT-PCR) and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the IL-6 gene polymorphism. RESULTS: We found that the IL-6 polymorphism rs12700386 enhanced patient susceptibility to developing knee OA. Based on a subgroup analysis, the risk of developing knee OA was elevated in smokers, drinkers, and subjects ≥55 years old or with BMI ≥ 25 kg/m2. The combination of smoking, drinking, and having the rs12700386 genotype led to an increase in the risk of developing knee OA, indicating that an underlying interaction between gene and environment exists. The rs12700386 genotype was found to be correlated with an increase in IL-6 expression. We also found that IL-6 levels were significantly higher in the CC genotype compared to the GG genotype carriers in OA patients. CONCLUSION: These data suggest that the rs12700386 polymorphism in the IL-6 gene leads to an increase in the risk of knee OA in Chinese Han individuals.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-6/genética , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/etnologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
18.
J Am Soc Nephrol ; 31(12): 2949-2963, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32912934

RESUMO

BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Pessoa de Meia-Idade , Proteína-Arginina Desiminase do Tipo 4/genética , Receptores Imunológicos/genética
19.
J Transl Med ; 18(1): 321, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32831104

RESUMO

BACKGROUND: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. METHODS: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program. RESULTS: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian. CONCLUSIONS: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.


Assuntos
Betacoronavirus/fisiologia , Mutação de Sentido Incorreto , Peptidil Dipeptidase A/genética , Domínios e Motivos de Interação entre Proteínas/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Substituição de Aminoácidos , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/metabolismo , Sítios de Ligação/genética , COVID-19 , Infecções por Coronavirus/etnologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Análise Mutacional de DNA/métodos , Bases de Dados Genéticas , Predisposição Genética para Doença/etnologia , Variação Genética , Geografia , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/etnologia , Pneumonia Viral/genética , Pneumonia Viral/virologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Estrutura Secundária de Proteína/genética , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus
20.
Dis Markers ; 2020: 1910215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32831971

RESUMO

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.


Assuntos
Artrite Reumatoide/genética , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Europa (Continente)/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão
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