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1.
Nutrients ; 13(6)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198753

RESUMO

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10-8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.


Assuntos
Densidade Óssea/genética , Fraturas Ósseas/sangue , Fraturas Ósseas/genética , Predisposição Genética para Doença/genética , alfa-Tocoferol/sangue , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Calcanhar/diagnóstico por imagem , Humanos , Masculino , Análise da Randomização Mendeliana , Metanálise como Assunto , Razão de Chances , Polimorfismo de Nucleotídeo Único , Ultrassonografia
2.
Nat Commun ; 12(1): 4198, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234117

RESUMO

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Locos de Características Quantitativas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Polimorfismo de Nucleotídeo Único
3.
Nat Genet ; 53(6): 840-860, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34059833

RESUMO

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.


Assuntos
Glicemia/genética , Grupo com Ancestrais do Continente Europeu/genética , Característica Quantitativa Herdável , Alelos , Epigênese Genética , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/metabolismo , Humanos , Herança Multifatorial/genética , Mapeamento Físico do Cromossomo , Locos de Características Quantitativas/genética
4.
J Ayub Med Coll Abbottabad ; 33(2): 322-327, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34137553

RESUMO

BACKGROUND: Osteoarthritis is regarded as one of the most frequent disorders of musculoskeletal, which is characterized by the degeneration of articular cartilage and loss of cartilage of the joints. However, the relationship of OA susceptibility with rs12901499 polymorphism in SMAD3 is controversial. Although multiple studies have investigated the correlation of rs12901499A/G polymorphism in SMAD family member 3 (SMAD3) andosteoarthritis (OA) susceptibility, the results from previous studies remain controversial and unsolved. A meta-analysis utilizing fixed and random effects model was performed to clarify the association. METHODS: Eligible studies were systematically searched from PubMed, Web of Science, Cochrane Library and EMBASE on April 17, 2019 for reporting the correlation of rs12901499 polymorphism and osteoarthritis susceptibility. Pooled Odds ratio of 95% confidence interval was performed to estimate the strength of relationship of rs12901499 polymorphism and osteoarthritis susceptibility. Publication bias was detected by Begg's test and STATA 11.0 software was used to evaluate statistical analysis. RESULTS: Seven case-control papers involving eight studies from Caucasian and Asian populations were included. A significant increase in osteoarthritis susceptibility was found in recessive, homozygous and allele models. Stratified analysis on ethnicity suggested that the polymorphism with increased risk of OA only in Asians under allele model. Stratified analysis related to population-based studies indicated the increased risk of OA with polymorphism in recessive, homozygous, allele and dominant models. CONCLUSIONS: This meta-analysis demonstrated that there may be a weak association of rs12901499 polymorphism and OA susceptibility. Due to the limited size of sample and given ethnic groups, more studies need to validate the result in future.


Assuntos
Predisposição Genética para Doença , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Proteína Smad3/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Razão de Chances
5.
PLoS Med ; 18(6): e1003605, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34061844

RESUMO

BACKGROUND: Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. METHODS AND FINDINGS: Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. CONCLUSIONS: In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.


Assuntos
COVID-19/sangue , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Adulto , Idoso , COVID-19/etiologia , Estudos de Casos e Controles , Causalidade , Suplementos Nutricionais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hospitalização , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , SARS-CoV-2 , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/genética
6.
Intensive Care Med ; 47(7): 761-771, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34032881

RESUMO

PURPOSE: Acute respiratory distress syndrome (ARDS) is accompanied by a dysfunctional immune-inflammatory response following lung injury, including during coronavirus disease 2019 (COVID-19). Limited causal biomarkers exist for ARDS development. We sought to identify novel genetic susceptibility targets for ARDS to focus further investigation on their biological mechanism and therapeutic potential. METHODS: Meta-analyses of ARDS genome-wide association studies were performed with 1250 cases and 1583 controls in Europeans, and 387 cases and 387 controls in African Americans. The functionality of novel loci was determined in silico using multiple omics approaches. The causality of 114 factors potentially involved in ARDS development was assessed using Mendelian Randomization analysis. RESULTS: There was distinct genetic heterogeneity in ARDS between Europeans and African Americans. rs7967111 at 12p13.2 was functionally associated with ARDS susceptibility in Europeans (odds ratio = 1.38; P = 2.15 × 10-8). Expression of two genes annotated at this locus, BORCS5 and DUSP16, was dynamic but ultimately decreased during ARDS development, as well as downregulated in immune cells alongside COVID-19 severity. Causal inference implied that comorbidity of inflammatory bowel disease and elevated levels of C-reactive protein and interleukin-10 causally increased ARDS risk, while vitamin D supplementation and vasodilator use ameliorated risk. CONCLUSION: Our findings suggest a novel susceptibility locus in ARDS pathophysiology that implicates BORCS5 and DUSP16 as potentially acting in immune-inflammatory processes. This locus warrants further investigation to inform the development of therapeutic targets and clinical care strategies for ARDS, including those induced by COVID-19.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Humanos , Síndrome do Desconforto Respiratório/genética , SARS-CoV-2
7.
J Drugs Dermatol ; 20(5): 504-510, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938707

RESUMO

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide. While most BCCs are treated surgically, advanced BCCs are often treated with gene-targeted therapies. While there has been a lot of research in BCC from Caucasian patients, research is lacking in patients with skin of color. OBJECTIVE: To identify potential variations in BCC gene mutations between Asian, Hispanic, and Caucasian patients. METHODS: A cohort study was performed from 2015 to 2017 with 23 patients treated for BCC at an urban academic hospital. Gene mutations were assessed using a targeted mutation panel for 76 cancer-associated genes from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: Groups studied comprised Asian (n=5), Hispanic (n=10), and Caucasian (n=8) patients. The Hispanic cohort had the highest number of mutations per patient on average (3.4 versus 2.8 for both Caucasian and Asian cohorts). GATA3 mutations were more prevalent in Hispanic patients (P=0.02, single factor ANOVA). ARID1A and PTEN mutations co-occurred in the Hispanic cohort (P<0.05). The most common mutation in the Asian cohort was TP53 (2/5). The Caucasian cohort had the highest percent of UVB mutations (68.4%). CONCLUSIONS: This study shows potential differences in the prevalence of somatic gene mutations for BCC patients of different races and ethnicities, which could inform the underlying pathogenesis, impact the efficacy of therapies in specific populations, and may also help identify novel therapeutic targets. J Drugs Dermatol. 20(5): doi:10.36849/JDD.5884.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Basocelular/genética , Análise Mutacional de DNA/estatística & dados numéricos , Neoplasias Cutâneas/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/patologia , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia
8.
Medicine (Baltimore) ; 100(20): e25922, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011063

RESUMO

BACKGROUND: Numerous studies have investigated the associations between Vitamin D receptor (VDR) gene polymorphisms and risk of intervertebral disc degeneration but the results remain controversial. This study aimed to drive a more precise estimation of association between VDR gene polymorphisms and risk of intervertebral disc degeneration. METHODS: PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated Database for papers on VDR gene polymorphisms and risk of intervertebral disc degeneration were searched. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive model. RESULTS: Overall, 23 articles were included in the final meta-analysis. The subgroup analyses by ethnicity showed a significant association of VDR FokI mutation with disc degeneration risk in Caucasians (recessive model, OR with 95%CI 1.301, [1.041, 1.626]; additive model, OR with 95%CI 1.119, [1.006, 1.245]). The results of subgroup analyses by ethnicity showed a significant association of VDR TaqI mutation with disc degeneration risk in Asians but not in Caucasians. There was a significant association between VDR ApaI mutation and risk of disc degeneration and subgroup analyses by ethnicity showed a significant association in Caucasians and in Asians. CONCLUSIONS: In summary, VDR FokI polymorphisms was associated with disc degeneration risk among Caucasians but not Asians, VDR TaqI polymorphisms was associated with disc degeneration risk among Asians but not Caucasians, while VDR ApaI polymorphism was associated with disc degeneration risk among Asians and Caucasians.


Assuntos
Predisposição Genética para Doença , Degeneração do Disco Intervertebral/genética , Dor Lombar/genética , Receptores de Calcitriol/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/epidemiologia , Dor Lombar/epidemiologia , Razão de Chances , Polimorfismo de Fragmento de Restrição
9.
Cardiovasc Ther ; 2021: 6667934, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025779

RESUMO

Background: It has been suggested that the angiotensinogen (AGT) gene rs4762 (p.Thr174Met) polymorphism might be associated with myocardial infarction (MI) risk, but the study results are still debatable. Objective and Methods. In order to explore the relationship between AGT p.Thr174Met polymorphism and MI risk, the current meta-analysis involving 7657 subjects from 11 individual studies was conducted. Results: A significant association between AGT p.Thr174Met polymorphism and MI was found under recessive (OR: 2.26, 95% CI: 1.35-3.77, P = 0.002), dominant (OR: 1.131, 95% CI: 1.016-1.260, P = 0.024), codominant (OR: 2.198, 95% CI: 1.334-3.621, P = 0.002), and additive (OR: 1.363, 95% CI: 1.132-1.641, P = 0.001) genetic models. In the Asian subgroup, significantly increased MI risk was found under all genetic models (P < 0.05). No significant association between AGT p.Thr174Met polymorphism and MI was found under all genetic models in the Caucasian subgroup (P > 0.05). Conclusions: AGT p.Thr174Met variant might increase MI risk, especially within the Asian population. The Met174 allele of AGT p.Thr174Met might confer the risk for MI.


Assuntos
Angiotensinogênio/genética , Predisposição Genética para Doença , Infarto do Miocárdio/genética , Polimorfismo Genético , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/etiologia , Fatores de Risco
10.
Sci Rep ; 11(1): 9905, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972602

RESUMO

The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, and mortality. Expression profiles represent snapshots of combined genetic, socio-environmental (including socioeconomic and environmental factors), and physiological effects on the molecular phenotype. As such, they have potential to improve biological understanding of differences among populations, and provide therapeutic biomarkers and environmental mitigation strategies. Here, we undertook a large-scale assessment of patterns of gene expression between African Americans and European Americans, mining RNA-Seq data from 25 non-diseased and diseased (tumor) tissue-types. We observed the widespread enrichment of pathways implicated in COVID-19 and integral to inflammation and reactive oxygen stress. Chemokine CCL3L3 expression is up-regulated in African Americans. GSTM1, encoding a glutathione S-transferase that metabolizes reactive oxygen species and xenobiotics, is upregulated. The little-studied F8A2 gene is up to 40-fold more highly expressed in African Americans; F8A2 encodes HAP40 protein, which mediates endosome movement, potentially altering the cellular response to SARS-CoV-2. African American expression signatures, superimposed on single cell-RNA reference data, reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. Our findings establish basal prognostic signatures that can be used to refine approaches to minimize risk of severe infection and improve precision treatment of COVID-19 for African Americans. To enable dissection of causes of divergent molecular phenotypes, we advocate routine inclusion of metadata on genomic and socio-environmental factors for human RNA-sequencing studies.


Assuntos
Afro-Americanos/genética , COVID-19/genética , Grupo com Ancestrais do Continente Europeu/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , COVID-19/epidemiologia , COVID-19/virologia , Quimiocina CCL3/genética , Redes Reguladoras de Genes , Glutationa Transferase/genética , Humanos , Neoplasias/classificação , Neoplasias/etnologia , Proteínas Nucleares/genética , Pandemias , Prognóstico , RNA-Seq/métodos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Fatores Socioeconômicos , Estados Unidos/epidemiologia
11.
Genes (Basel) ; 12(3)2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808521

RESUMO

The genetic signature of modern Europeans is the cumulated result of millennia of discrete small-scale exchanges between multiple distinct population groups that performed a repeated cycle of movement, settlement, and interactions with each other. In this study we aimed to highlight one such minute genetic cycle in a sea of genetic interactions by reconstructing part of the genetic story of the migration, settlement, interaction, and legacy of what is today the Transylvanian Saxon. The analysis of the mitochondrial DNA control region of 13 medieval individuals from Feldioara necropolis (Transylvania region, Romania) reveals a genetically heterogeneous group where all identified haplotypes are different. Most of the perceived maternal lineages are of Western Eurasian origin, except for the Central Asiatic haplogroup C seen in only one sample. Comparisons with historical and modern populations describe the contribution of the investigated Saxon settlers to the genetic history of this part of Europe.


Assuntos
DNA Antigo/análise , DNA Mitocondrial/história , Grupo com Ancestrais do Continente Europeu/genética , Mitocôndrias/genética , Ásia/etnologia , DNA Mitocondrial/genética , Genética Populacional , História Medieval , Humanos , Filogenia , Dinâmica Populacional , Romênia/etnologia
12.
Nat Immunol ; 22(5): 654-665, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33888898

RESUMO

Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161+CD4+ T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4+ T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.


Assuntos
Imunidade Adaptativa/imunologia , Suscetibilidade a Doenças/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Imunidade Adaptativa/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Células Dendríticas/imunologia , Suscetibilidade a Doenças/sangue , Suscetibilidade a Doenças/parasitologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Voluntários Saudáveis , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon gama/metabolismo , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , RNA-Seq , Análise de Sistemas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
13.
Medicine (Baltimore) ; 100(17): e25689, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907143

RESUMO

BACKGROUND: An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE. METHODS: Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684-0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed. CONCLUSIONS: Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a2 rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Razão de Chances
14.
Eur J Endocrinol ; 185(1): R1-R11, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33900205

RESUMO

Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing has resulted in the identification of somatic mutations in aldosterone-producing adenoma (APA), a major subtype of PA. Based on the recent findings using a sequencing method that selectively targets the tumor region where aldosterone synthase (CYP11B2) is expressed, the vast majority of APAs appear to harbor a somatic mutation in one of the aldosterone-driver genes, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. Mutations in these genes alter intracellular ion homeostasis and enhance aldosterone production. In a small subset of APAs, somatic activating mutations in the CTNNB1 gene, which encodes ß-catenin, have also been detected. Accumulating evidence suggests that race and sex impact the somatic mutation spectrum of APA. Specifically, somatic mutations in the KCNJ5 gene, encoding an inwardly rectifying K+ channel, are common in APAs from Asian populations as well as women regardless of race. Associations between APA histology, genotype, and patient clinical characteristics have also been proposed, suggesting a potential need to consider race and sex for the management of PA patients. Herein, we review recent findings regarding somatic mutations in APA and discuss potential roles of race and sex on the pathophysiology of APA as well as possible clinical implications.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Grupos de Populações Continentais/genética , Hiperaldosteronismo/genética , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/etnologia , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/etnologia , Afro-Americanos/genética , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo T/genética , Canais de Cloreto/genética , Citocromo P-450 CYP11B2/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Humanos , Hiperaldosteronismo/etnologia , Hiperaldosteronismo/etiologia , Masculino , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Fatores Sexuais , ATPase Trocadora de Sódio-Potássio/genética , Esteroide 11-beta-Hidroxilase/genética , beta Catenina/genética
15.
Nutrients ; 13(4)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920682

RESUMO

(1) Background: Lactose digestion depends on persistence genotypes (including rs4988235), the frequency of which exhibits broad geographical variability. However, little is known about the relationship between lactase (LCT) genotypes and intestinal expression of LCT. We aimed to investigate ileal expression of LCT depending on main genetic polymorphisms (rs4988235, rs3754689, rs3739022), age, sex, smoking status, body mass index (BMI), and the expression of other genes; (2) Methods: phenotype, array-based genotype, and ileal mucosal biopsy expression data were obtained from the CEDAR study; (3) Results: analyses included 196 healthy Europeans (53.6% women) aged 53.0 ± 13.6 years with a mean BMI of 25.6 ± 4.2 kg/m2, of whom 17.4% were smoking. Ileal LCT expression was mostly independent of age, sex, BMI, or smoking. Rs4988235 homozygous minor allele (GG) associated with lower LCT expression (vs. AG p = 2.2 × 10-6, vs. AA p = 1.1 × 10-7). Homozygous major allele of rs3754689 (GG) was related to higher LCT expression (vs. AG p = 1.7 × 10-5, vs. AA p = 0.0074). Rs3754689 genotype did not modify LCT expression (GG vs. AG p = 0.051) in rs4988235-heterozygous subgroup. Interestingly, CD14, which is a marker of monocytes and macrophages, was the strongest negative transcriptomic correlate of LCT expression (r = -0.57, pFDR = 1.1 × 10-14); (4) Conclusions: both rs4988235 and rs3754689 associated with ileal LCT expression, which did not seem related to age, sex, smoking, or BMI. The inverse correlation between LCT and CD14 expression in the ileum is striking and requires further investigation.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Lactase/genética , Polimorfismo Genético , Adulto , Fatores Etários , Idoso , Biópsia , Índice de Massa Corporal , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores Sexuais
16.
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
17.
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
18.
Genes (Basel) ; 12(2)2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671795

RESUMO

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA HGB8P were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , RNA não Traduzido/genética , Afro-Americanos/genética , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Variações do Número de Cópias de DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Genoma
19.
Am J Phys Anthropol ; 175(2): 497-505, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33704773

RESUMO

OBJECTIVES: While genetic studies have documented variation in admixture proportions in contemporary African Americans across the US, relatively little is known about the socio-historical roots of this variation. Our goal in this study is to use dental morphology to explore the socio-historical correlates of admixture, localized gene flow, and drift in African Americans. METHODS: Our data are ordinally-graded dental morphological traits scored in 196 Africans, 335 Europeans and European Americans, 291 pre-Spanish-contact Native Americans, and 722 African Americans. The African American data derived from contemporary and historic samples. We eliminated from analysis individuals and traits with greater than 20% missing data. We summarized the major axes of trait variation using principal component analysis (PCA), estimated biological distance, constructed multidimensional scaling (MDS) plots of the distances, and measured the correlation between geographic and biological distance. RESULTS: In the PCA, African American groups clustered between Africans and Europeans on PC 1, reflecting admixture between the groups. PC 2 separated African American samples, possibly reflecting movement, isolation, and drift. MDS analyses confirmed the existence of sizable biological distances between African American samples, especially between contemporary and past African American samples. We found no relationship between biological and geographic distances. DISCUSSION: We demonstrate that admixture and drift can be inferred from multi-variable analyses of patterns of dental morphology in admixed populations. Localized gene flow has not affected patterns of trait variation in African Americans, but long-range movement, isolation, and drift have. We connect patterns of dental trait variation to efforts to flee oppression during the Great Migration, and the repeal of anti-miscegenation laws.


Assuntos
Afro-Americanos , Fluxo Gênico/genética , Genética Populacional , Dente/anatomia & histologia , Afro-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Antropologia Física , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Humanos
20.
Circ Heart Fail ; 14(3): e007537, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33724884

RESUMO

BACKGROUND: Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. METHODS: We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. RESULTS: Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m2, P<0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P=0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P<0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P=0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P<0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P=0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7, whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P<0.0001). CONCLUSIONS: There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine-based care of individuals with hypertrophic cardiomyopathy.


Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Grupos Étnicos/genética , Disparidades em Assistência à Saúde/etnologia , Adulto , África do Norte/etnologia , Grupo com Ancestrais do Continente Africano/genética , Idoso , Ásia/etnologia , Ásia Ocidental/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Austrália , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/etnologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/terapia , Proteínas de Transporte/genética , Desfibriladores Implantáveis/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/genética , Extremo Oriente/etnologia , Feminino , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio/etnologia , Cadeias Pesadas de Miosina/genética , Grupo com Ancestrais Oceânicos/genética , Estudos Retrospectivos
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