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1.
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 , Betacoronavirus/metabolismo , Sítios de Ligação/genética , 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 , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus
2.
Nat Genet ; 52(7): 669-679, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32514122

RESUMO

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Variação Genética , Humanos , Padrões de Herança , Japão , Masculino , Fatores Sexuais , Fatores de Transcrição/genética
3.
Medicine (Baltimore) ; 99(19): e19980, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384449

RESUMO

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with bladder cancer (BCa) risk in Caucasian and East Asian population. The objective of this study was to validate these SNPs in Chinese population and evaluate whether these SNPs could differentiate the individual inherited risk for BCa.A case-control study including 581 BCa cases and 1561 healthy controls was performed. Germline DNA samples from all individuals were genotyped for eight SNPs. Genetic risk score (GRS) was calculated for each individual based on the odds ratios and risk allele frequencies of five risk-associated SNPs.Among eight SNPs evaluated in this study, rs798766 at 4p16.3 [OR = 1.39 (1.15-1.67), P < .001], rs9642880 [OR = 1.17 (1.06-1.30), P < .001] and rs4813953 at 20p12.2 [OR = 1.09 (1.02-1.17), P = .016] were found associated with BCa risk in Chinese population. A genetic risk score was established based on five SNPs (including the above three SNPs and two other SNPs which have the consistent direction with previous reported genome-wide association study). The mean GRS was significantly higher in BCa cases than controls (1.22 vs. 1.01, P < .001). When subjects were categorized into low- (<0.8), average- (0.8-1.2), and high-risk (>1.2) groups, the likelihoods of BCa were 25.2%, 33.7% and 55.0%, respectively (P-trend < 2.2 × 10). In subgroup analyses, no significant difference was observed in mean GRS among BCa patients with different stages or grades.In conclusion, two SNPs derived from East Asian and one SNP from Caucasian were associated with BCa risk in Chinese population. These results provided additional information of genetic risks for BCa in Chinese population. Genetic risk score based on these SNPs can reveal inherited risk of BCa, and may have potential for modifying personalized cancer screening strategy.


Assuntos
Predisposição Genética para Doença/etnologia , Proteínas Associadas aos Microtúbulos/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco/métodos , Neoplasias da Bexiga Urinária/etnologia , Neoplasias da Bexiga Urinária/genética
5.
Best Pract Res Clin Obstet Gynaecol ; 65: 139-153, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32245629

RESUMO

Germline mutations in cancer-susceptibility-genes (CSG) can dramatically increase womens' lifetime risk of ovarian, endometrial, breast and bowel cancers. Identification of unaffected carriers is important to enable proactive engagement with highly effective screening and preventive options to minimise cancer risk. Currently, a family-history model is used to identify individuals with CSGs. Complex regional referral guidelines specify the family-history criteria required before an individual is eligible for genetic-testing. This model is ineffective, resource intense, misses >50% CSG carriers, is associated with underutilisation of genetic-testing services and delays detection of mutation carriers. Although awareness and detection of CSG-carriers has improved, over 97% carriers remain unidentified. This reflects significant missed opportunities for precision-prevention. Population-based genetic-testing (PBGT) represents a novel healthcare strategy with the potential to dramatically improve detection of unaffected CSG-carriers along with enabling population risk-stratification for cancer precision-prevention. Several research studies have assessed the impact, feasibility, acceptability, long-term psychological outcomes and cost-effectiveness of population-based BRCA-testing in the Ashkenazi-Jewish population. Initial data on PBGT in the general-population is beginning to emerge and large implementation studies investigating PBGT in the general-population are needed. This review will summarise the current research into the clinical, psycho-social, health-economic, societal and ethical consequences of a PBGT model for women's cancer precision-prevention.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença/etnologia , Testes Genéticos/métodos , Genética Populacional , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Neoplasias Ovarianas/genética , Neoplasias da Mama/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Humanos , Mutação , Neoplasias , Neoplasias Ovarianas/diagnóstico
6.
Ann Rheum Dis ; 79(5): 657-665, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32238385

RESUMO

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Aldeído-Desidrogenase Mitocondrial/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Gota/genética , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Loci Gênicos , Genótipo , Gota/epidemiologia , Humanos , Incidência , Japão , Masculino , Fenótipo , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença
7.
Medicine (Baltimore) ; 99(11): e19433, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176070

RESUMO

BACKGROUND: Number of studies have been performed to evaluate the relationship between the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) gene variant rs5742909 polymorphism and cervical cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association. METHODS: PubMed, Web of Science, Embase, China Biology Medical Literature database, China National Knowledge Infrastructure, WanFang, and Weipu databases were searched before July 31, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0. RESULTS: Eleven studies involved 3899 cases and 4608 controls. Overall, significant association was observed between the CTLA-4 gene variant rs5742909 polymorphism and cervical cancer (T vs C: OR = 1.40, 95% CI = 1.12-1.76; TT vs CC: OR = 2.22, 95% CI = 1.13-4.37; TT vs CT+CC: OR = 1.96, 95% CI = 1.03-3.74; TT+CT vs CC: OR = 1.47, 95% CI = 1.14-1.90). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR = 1.56, 95% CI = 1.22-1.99), but not in Caucasians (T vs C: OR = 1.19, 95% CI = 0.87-1.62). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. CONCLUSION: our meta-analysis supports that the CTLA-4 gene variant rs5742909 polymorphism might contribute to individual susceptibility to cervical cancer in Asians.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Antígeno CTLA-4/genética , Predisposição Genética para Doença/etnologia , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/genética , Feminino , Humanos
8.
Gynecol Obstet Invest ; 85(2): 167-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32114577

RESUMO

INTRODUCTION: The goal of this study was to review relevant case-control trials in order to determine the association of paraoxonase 1 (PON1) gene polymorphisms (-108C/T, 55L/M, 192Q/R) and polycystic ovarian syndrome (PCOS) susceptibility. METHODS: Using appropriate keywords, we identified relevant studies using PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP. Key pertinent sources in the literature were also reviewed, and all articles published through April 2019 were considered for inclusion. Based on the qualified studies, we performed a meta-analysis of associations between -108C/T, 55L/M and 192Q/R polymorphisms in PON1 and risk of PCOS. RESULTS: We included 13 case-control studies with 3,660 total patients in the PCOS group and 2,835 in the control group. These studies found that the population with -108C/T locus T were associated with lower PCOS susceptibility by heterozygote model (OR 0.442, 95% CI 0.259-0.754); the Caucasian population with -108C/T locus T were associated with higher PCOS susceptibility by regressive model (OR 2.087, 95% CI 1.242-3.504). The population with 55L/M locus M were associated with higher PCOS susceptibility by regressive model (OR 1.518, 95% CI 1.067-2.160); the Asian population with 55L/M locus M were associated with lower PCOS susceptibility by dominant model and heterozygote model. The population with 192Q/R locus R were associated with higher PCOS susceptibility by the 5 gene models. The Asian population with 192Q/R locus R were associated with higher PCOS susceptibility: allelic model (OR 1.271, 95% CI 1.139-1.417); homozygote model (OR 1.575, 95% CI 1.244-1.995); dominant model (OR 1.299, 95% CI 1.069-1.580); regressive model (OR 1.421, 95% CI 1.207-1.673). The Caucasian population with 192Q/R locus R were associated with higher PCOS susceptibility: heterozygote model (OR 2.113, 95% CI 1.266-3.526). CONCLUSION: Our meta-analysis suggested that 192Q/R locus R were associated with higher PCOS susceptibility in both the Asian and Caucasian population.


Assuntos
Arildialquilfosfatase/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/genética , Síndrome do Ovário Policístico/genética , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/etnologia , Heterozigoto , Humanos , Síndrome do Ovário Policístico/etnologia , Polimorfismo Genético
9.
Acta Diabetol ; 57(6): 733-741, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32025861

RESUMO

AIMS: The milk fat globule-epidermal growth factor 8 (MFGE8), also called lactadherin, is an integrin ligand and a known mediator of inflammation and atherosclerosis in T2DM in studies using animal models. However, its role in the pathophysiology of human T2DM, obesity, and cardiovascular disease has been poorly explored. Aim of this study  was to investigate the role of a missense variant (rs371227978 C/T: Arg148His) in the MFGE8 gene identified through exome sequencing for its association with T2DM and cardiometabolic traits. METHODS: Exome-wide sequencing was performed using DNA samples from 68 Sikh individuals from multi-generation pedigrees affected with diabetes on Illumina's GAIIx using "SureSelect Human All Exon" panels. We further replicated this variant by de novo genotyping in a total of 4242 individuals of the Asian Indian Diabetic Heart Study/Sikh Diabetes Study using custom TaqMan genotyping assay. We also measured circulating concentrations of Mfge8 using frozen serum aliquots by enzyme-linked immunosorbent assay. RESULTS: Overall, only 1.78% of 4242 individuals were carriers of this variant with MAF being 0.009. Except for the significant correlation of this variant with T2DM and triglycerides, no other quantitative risk phenotype was significant. The minor per allele-associated increased risk for T2DM showed odds ratio of 1.95 (95% CI 1.18-3.23; p = 0.008) in unadjusted model and was 1.73 (95% CI 1.02-2.93; p = 0.043) after adjusting for the age, gender, and BMI. However, there was a strong correlation between serum Mfge8 concentrations with T2DM, (r2 = 0.38; p = 0.001), fasting glucose (r2= 0.36; p = 0.002), and triglycerides (r2 = 0.33; p = 0.005). Our data revealed a significant dose-related increase in MFGE8 genotypes for affecting serum Mfge8 (p = 2.1 × 10-3) and triglyceride concentrations (p = 3.2 × 10-3). For a per risk allele-associated increase of 4.74 ng/ml ± SD of 1.62 ng/ml of the Mfge8 concentration was found to increase T2DM risk to 1.7 fold (95% CI from 1 to 3 fold). CONCLUSIONS: Here, we report for the first time a novel population-specific rare variant in the MFGE8 gene linked with the increased Mfge8 concentrations and the risk for developing T2DM and cardiovascular risk factors in a population of Punjabi Sikhs from India. In view of a strong evidence from animal studies supporting the role of Mfge8 in obesity, insulin resistance, and the development of atherosclerosis in T2DM, our findings are important and timely. If validated in a large independent dataset, early screening of Mfge8 in blood levels may especially benefit those patients with genetically elevated Mfge8 levels to preventing or reducing the risk of T2DM and cardiovascular disease.


Assuntos
Antígenos de Superfície/genética , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Grupos Étnicos/genética , Proteínas do Leite/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Doenças Cardiovasculares/etnologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/etnologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/etnologia , Genética Populacional , Genótipo , Humanos , Índia/epidemiologia , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
10.
BMC Oral Health ; 20(1): 58, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075624

RESUMO

BACKGROUND: Chronic periodontitis (CP) is an immune-inflammatory disease that promotes tissue damage around the teeth. Among the several inflammatory mediators that orchestrate the periodontitis, there is the interleukin (IL)-2. Genetic variations in IL2 gene may be associated with the risk and severity of the disease. Contrary results are available in the literature with inconclusive findings and none meta-analysis to gather these data. METHODS: A literature search was performed for studies published before June 11, 2019 in diverse scientific and educational databases. The data was extracted by two investigators and the statistical evaluation was performed by Review Manager statistical program with heterogeneity (I2) and Odds Ratio (OR) with 95% of Confidence Intervals (CI) calculations and a sensitive analysis to assess the accuracy of the obtained results. The publication bias was evaluated by Begg' and Egger's test with Comprehensive meta-analysis software. The value of P < 0.05 was considered as significant. RESULTS: Five studies were identified in diverse ethnical groups with 1425 participants. The - 330 T/G polymorphism in IL2 gene was not significantly associated with CP in allelic evaluation (P > 0.05) as well as in the genotypic comparisons (P = 0.15). The Begg's test and the linear regression Egger's test did not show any evidence of publication bias risk (P > 0.05) which was corroborated by the absence of obvious asymmetry in Funnel plot graphic. CONCLUSIONS: This meta-analysis showed a non-significant association between - 330 T/G polymorphism in IL2 gene and CP in any allelic evaluation.


Assuntos
Periodontite Crônica/genética , Predisposição Genética para Doença/genética , Interleucina-2/genética , Alelos , Predisposição Genética para Doença/etnologia , Humanos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Nat Commun ; 11(1): 255, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937769

RESUMO

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.


Assuntos
Variações do Número de Cópias de DNA , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Hibridização Genômica Comparativa , Bases de Dados Genéticas , Loci Gênicos , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único
12.
DNA Cell Biol ; 39(1): 92-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31721599

RESUMO

There is increasing evidence suggesting that dysregulation of miR-155 and its target angiotensin receptor type 1 (AT1R) are linked to the incidence of ischemic stroke (IS), but the underlying mechanisms remain to be clarified. In this study, we therefore sought to investigate how miR-155 and AT1R polymorphisms affect IS risk. We included 579 IS patients and 509 age-matched controls in the present analysis, genotyping individuals for the rs767649 polymorphism in miR-155, as well as for the rs1492099 and rs275653 polymorphisms in AT1R via iMLDR-TM genotyping technology. The allele and genotype frequencies for the assessed polymorphisms were comparable in IS patients and controls, without any detectable association between AT1R haplotype and IS risk. We conducted additional trial of ORG 10172 in acute stroke treatment-mediated stratification, which indicated that the AT1R rs1492099 T allele was linked to a decreased risk of large-artery atherosclerosis (LAA) stroke. We further found that those with the AT1R rs275653 AA genotype had a decreased risk of small-artery occlusion (SAO) strokes. We further confirmed elevated miR-155 expression in IS patients, but observed no link between the rs767649 polymorphism and expression of this microRNA. Similarly, rs1492099 and rs275653 polymorphisms did not impact AT1R expression levels. The miR-155 rs767649 polymorphism does not seem to be a key determinant of IS risk, whereas the AT1R rs1492099 polymorphism is linked to reduced LAA-stroke risk, and the rs275653 AA genotype is potentially protective against SAO strokes.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Angiotensina/genética , Acidente Vascular Cerebral/genética , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/complicações , China , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etnologia
13.
DNA Cell Biol ; 39(1): 57-62, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794672

RESUMO

Mycobacterium tuberculosis (Mtb) is the causative agent of the disease tuberculosis (TB). Macrophages eliminate the Mtb, delivering it to the degradative, phagolysosomal compartment for degradation, in which reactive oxygen species generated by nicotinamide adenine dinucleotide phosphate oxidase (NADPHO) plays an important role. In our study, we aimed at investigating the association of polymorphisms in neutrophil cytosolic factor 2 (NCF2) gene, the core component of NADPHO, with susceptibility of TB in the Western Chinese Han population. We conducted a case-control study of 900 cases and 1534 controls and genotyped four single-nucleotide polymorphisms within the NCF2 gene. We found that the rs10911362 variants were associated with a decreased TB risk in this population (odds ratio [ORG] = 0.83 [0.72-0.95], ORadd = 0.83 [0.72-0.95], ORdom = 0.78 [0.66-0.93], p < 0.05). rs10911362 might fall in a transcriptional factor binding site associated with ZNF410 and may be the expression quantitative trait loci (eQTL) for the SMG7 gene according to the Ensembl data. Our study demonstrated for the first time that the G allele of NCF2 rs10911362 provided a protective role against TB risk in the Western Chinese Han population.


Assuntos
Predisposição Genética para Doença/genética , NADPH Oxidases/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Adulto , Alelos , 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 , Tuberculose/etnologia , Adulto Jovem
14.
DNA Cell Biol ; 39(1): 63-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31855460

RESUMO

To investigate the contribution of de novo variants to Tourette disorder (TD) probands in China. Whole-exome sequencing (WES) conducted on 15 child-parent trios (45 samples) detected 25 coding de novo variants, including 2 de novo Likely Gene Disrupting (LGD) variants and 6 Missense3 variants. The de novo LGD variants were consistently associated with TD risk (Fisher's exact test OR 2.69; p = 0.1952), although statistical significance was not achieved due to the small sample size. We then assessed the relationship between the genetic events and phenotypic data by comparing Yale Global Tic Severity Scale (YGTSS) scores. The TD probands with damaging variants (defined as LGD variants and Mis3 variants) had significantly higher YGTSS scores, suggesting more severe tic symptoms (p = 0.019). We also observed a hit for a damaging compound heterozygous (CH) mutation in CELSR3, a high-confidence TD risk gene, in one of the TD probands. To our knowledge, this is the first study to investigate de novo variants in TD in a Chinese population. Our results showed that de novo LGD variants contributed to TD risk in our cohort and that TD probands with de novo damaging variants have more severe symptoms. Furthermore, our observation of damaging CH mutations in CELSR3 in an individual affected with TD further strengthened the confidence in a role for this gene in TD etiology.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Síndrome de Tourette/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Caderinas/genética , China , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Heterozigoto , Humanos , Masculino , Receptores de Superfície Celular/genética , Síndrome de Tourette/etnologia , Adulto Jovem
15.
Rheumatology (Oxford) ; 59(1): 90-98, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31236574

RESUMO

OBJECTIVE: LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). METHODS: Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. RESULTS: Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). CONCLUSION: We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.


Assuntos
Idade de Início , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Adolescente , Adulto , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/etnologia , Nefrite Lúpica/etnologia , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
16.
Medicine (Baltimore) ; 98(50): e18408, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852161

RESUMO

BACKGROUND: Several studies have explored the associations between interleukin-6 (IL-6) gene polymorphisms and the susceptibility to liver diseases, however, results remain ambiguous. The goal of this study was to conduct a meta-analysis to provide more credible evidence. METHODS: Studies identified in the PubMed, Cochrane Library, and EMBASE databases were used to perform a meta-analysis via the STATA software. Pooled odds ratios (OR) were calculated under fixed- and random-effects models to estimate the potential genetic associations. RESULTS: Twenty-five case-control studies involving 5813 cases and 5298 controls were included in this meta-analysis. Overall, the pooled results suggested that rs1800795 polymorphism was significantly associated with the risk of liver diseases in heterozygote (GC vs CC; OR = 1.57) and dominant (GG+GC vs CC: OR = 1.47) models; rs1800796 polymorphism was significantly associated with the susceptibility to liver diseases in heterozygote (GG vs GC; OR = 0.58) and recessive (GG vs GC+CC: OR = 0.68) models; rs1800797 polymorphism was significantly associated with genetic predisposition to liver diseases in homozygote (GG vs AA: OR = 1.63), heterozygote (GA vs AA; OR = 1.53) and dominant (GG + GA vs AA: OR = 1.61) models. A similar conclusion was found in the HBV, HCV, HCC, NASH and alcoholic liver disease of all ethnic populations for rs1800795; HBV and Asian subgroups for rs1800796; HCV and non-Asian subgroups for rs1800797. However, IL-6 rs2069837 and rs2066992 polymorphisms did not exhibit significant associations with the risk of liver diseases under any genetic models. CONCLUSION: This meta-analysis suggests that patients carrying G (rs1800795), C (rs1800796) or G (rs1800797) allele or genotypes of IL-6 may be more likely to suffer from liver diseases, which was ethnic-dependent.


Assuntos
Interleucina-6/genética , Hepatopatias/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/etnologia , Humanos , Hepatopatias/etnologia , Polimorfismo de Nucleotídeo Único
17.
Nat Commun ; 10(1): 4719, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624269

RESUMO

Mosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10-6). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10-6). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10-6). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY.


Assuntos
Diferenciação Celular/genética , Deleção Cromossômica , Cromossomos Humanos Y/genética , Estudo de Associação Genômica Ampla/métodos , Células-Tronco Hematopoéticas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Plaquetas/citologia , Plaquetas/metabolismo , Estudos de Coortes , Eritrócitos/citologia , Eritrócitos/metabolismo , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Células-Tronco Hematopoéticas/citologia , Humanos , Japão , Masculino , Mosaicismo , Polimorfismo de Nucleotídeo Único
18.
Clin Lab ; 65(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625355

RESUMO

BACKGROUND: Association studies of tumor necrosis factor (TNF)-308 G/A (rs1800629) polymorphism and chronic obstructive pulmonary disease (COPD) have shown inconsistent and contradictory results among different populations. In the present study, a meta-analysis was performed to evaluate the association between TNF-308 G/A polymorphism and COPD susceptibility in Chinese population. MATERIALS AND METHODS: Systemic assessment was performed for the published studies from PubMed, Embase, Web of Science, the Cochrane Library, Wanfang Data, and CNKI prior to July 2018. Odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled using STATA software. RESULTS: A total of eighteen studies comprising 1,817 COPD cases and 2,056 controls were included in this meta-analysis. Overall, significant results were obtained between TNF-308 G/A polymorphism and COPD risk in Chinese population (A vs. G, OR = 2.45, 95% CI: 1.93 - 3.11; AA vs. GG, OR = 4.53, 95% CI: 2.67 - 7.68; AA vs. GA + GG, OR = 3.74, 95% CI: 2.21 - 6.33; AA + GA vs. GG, OR = 2.53, 95% CI: 1.97 - 3.26) under allele and homozygote models as well as recessive and dominant models. In the subgroup analyses, TNF-308 G/A polymorphism was significantly associated with increased COPD risk both in North China and South China, as well as in population-based studies. CONCLUSIONS: This meta-analysis indicates that TNF-308A/G polymorphism may contribute to individual suscepti-bility to COPD in Chinese population.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Necrose Tumoral alfa/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Desequilíbrio de Ligação , Razão de Chances , Doença Pulmonar Obstrutiva Crônica/etnologia , Fatores de Risco
19.
Medicine (Baltimore) ; 98(42): e17327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626088

RESUMO

To explore the association of a disintegrin and metalloprotease 33 (ADAM33) polymorphisms with childhood asthma susceptibility, we conducted this case-control study.In this case-control study, we selected 96 asthma children and 86 healthy children to conduct the genotyping of ADAM33 polymorphisms through polymerase chain reaction-direct sequencing (PCR-DS). Hardy-Weinberg equilibrium (HWE) status in the control group was detected adopting chi-square test. Frequency differences of genotypes, alleles, and haplotypes were compared by chi-square test between the case and control groups. Linkage disequilibrium (LD) between polymorphisms was checked using Haploview software. Association intensity of the polymorphisms with the disease risk was assessed by odds ratio (OR) and 95% confidence interval (95%CI).The frequency of rs678881 GA genotype was obviously higher in cases than in controls (P = .03) and the carriage of this genotype conferred higher risk of asthma among children than GG genotype (OR = 2.03, 95%CI = 1.05-3.91). However, neither rs2280089 nor rs2853209 polymorphism was significantly associated with the risk of childhood asthma. Strong LD was found among rs678881, rs2280089 and rs2853209, and haplotype GGT was distinctly associated with the risk of asthma in children (OR = 0.28, 95%CI = 0.13-0.57).ADAM33 rs678881 polymorphism is significantly correlated with increased susceptibility to asthma in Chinese Han children. Besides, haplotype GGT among the 3 polymorphisms was obviously associated with decreased risk of childhood asthma.


Assuntos
Proteínas ADAM/genética , Asma/genética , Alelos , Asma/sangue , Asma/etnologia , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Haplótipos , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
Asian J Psychiatr ; 46: 54-61, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31614268

RESUMO

Several studies have investigated association of MTHFR 677C > T and 1298A > C polymorphisms with risk of autism, but they have reported controversial and inconclusive results. The present meta-analysis was designed to evaluate association of MTHFR 677C > T and 1298A > C polymorphisms with risk of autism. A comprehensive literature search was done in PubMed, EMBASE, and CNKI databases to identify all eligible publications up to April 01, 2019. Finally, 25 case-control studies including 18 studies on MTHFR 677C > T and 7 studies on MTHFR 1298A > C polymorphism were selected. Overall, a significant association was found between MTHFR 677C > T and an increased risk of autism under all five genetic models (T vs. C: OR = 1.483, 95% CI 1.188-1.850, p ≤ 0.001; TT vs. CC: OR = 1.834, 95% CI 1.155-2.913, p = 0.010; TC vs. CC: OR = 1.512, 95% CI 1.101-2.078, p = 0.011; TT + TC vs. CC: OR = 1.632, 95% CI 1.261-2.113, p ≤ 0.001; and TT vs. TC + CC: OR = 1.427, 95% CI 1.002-2.032, p = 0.049). However, no significant association was found between MTHFR 1298A > C and autism risk. Stratified analyses showed that MTHFR 677C > T and 1298A > C polymorphisms are involved in genetic susceptibility of autism by ethnicity. Results of this meta-analysis indicated that MTHFR 677C > T polymorphism may be associated with increased risk of autism in overall and by ethnicity, while MTHFR 1298A > C was reported to be significantly associated with the risk of autism only in Caucasians. MTHFR polymorphisms could be used as a diagnostic marker for autism with respect to ethnicity background.


Assuntos
Transtorno do Espectro Autista/etnologia , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Humanos
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