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[PMID]:29335400
[Au] Autor:Zhu Z; Zheng Z; Zhang F; Wu Y; Trzaskowski M; Maier R; Robinson MR; McGrath JJ; Visscher PM; Wray NR; Yang J
[Ad] Endereço:Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
[Ti] Título:Causal associations between risk factors and common diseases inferred from GWAS summary data.
[So] Source:Nat Commun;9(1):224, 2018 01 15.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer's disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).
[Mh] Termos MeSH primário: Índice de Massa Corporal
Colesterol/sangue
Doença/genética
Estudo de Associação Genômica Ampla/métodos
[Mh] Termos MeSH secundário: Doença de Alzheimer/sangue
Doença de Alzheimer/genética
LDL-Colesterol/sangue
Diabetes Mellitus Tipo 2/sangue
Diabetes Mellitus Tipo 2/genética
Doença/etiologia
Seres Humanos
Análise da Randomização Mendeliana
Polimorfismo de Nucleotídeo Único
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholesterol, LDL); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02317-2


  2 / 468 MEDLINE  
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[PMID]:29390354
[Au] Autor:Li Z; Liu C; Shi X; Chen Z; Wang D; Li L; Tu Y; Lin M; Liu S; Yang S; Li X
[Ad] Endereço:Xiamen Diabetes Institute.
[Ti] Título:Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults.
[So] Source:Medicine (Baltimore);96(50):e9234, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Elevated serum fetuin-B is suggested to be associated with insulin resistance, but it is unknown if this association is causal. The aim of this study was to explore the potential causal relationship between fetuin-B and insulin resistance.We used Mendelian randomization analysis by incorporating information of genetic variants in FETUB and serum fetuin-B concentrations with insulin resistance in 1148 obese Chinese adults.Common genetic variants (FETUB rs4686434, rs6785067, and rs3733159) were significantly associated with serum fetuin-B concentrations but not with insulin resistance. Higher serum fetuin-B levels were significantly associated with increased homeostasis model assessment of insulin resistance (HOMA-IR) (0.17 [95%CI: 0.01 to 0.32, P = .037] 10 mol IU L higher per SD). However, Mendelian randomization analysis using 3 single-nucleotide polymorphisms as instrumental variables did not support a significant association between genetically predicted fetuin-B levels and HOMA-IR (-0.09 [95%CI: -0.62 to 0.44, P = .738] 10 mol IU L lower per SD). The regression coefficients for measured and genetically predicted fetuin-B concentrations on HOMA-IR were significantly different (P <.001).This study suggests the association between fetuin-B and insulin resistance may not be causal. Future studies on the nongenetic determinants of serum fetuin-B concentration to assess if such unmeasured factors may confound the association between fetuin-B and insulin resistance as well as more pathway analysis for this association are warranted.
[Mh] Termos MeSH primário: Fetuína-B/genética
Variação Genética
Resistência à Insulina/genética
Obesidade/genética
[Mh] Termos MeSH secundário: Adulto
Antropometria
Biomarcadores/sangue
China
Feminino
Genótipo
Seres Humanos
Masculino
Análise da Randomização Mendeliana
Obesidade/sangue
Polimorfismo de Nucleotídeo Único
Fatores de Risco
Inquéritos e Questionários
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Fetuin-B)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009234


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[PMID]:28742912
[Au] Autor:Larsson SC; Burgess S; Michaëlsson K
[Ad] Endereço:Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
[Ti] Título:Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction.
[So] Source:JAMA;318(4):371-380, 2017 Jul 25.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction. Objective: To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization. Design, Setting, and Participants: The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis. Exposures: Genetic risk score based on genetic variants related to elevated serum calcium levels. Main Outcomes and Measures: Co-primary outcomes were the odds of CAD and myocardial infarction. Results: Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction. Conclusions and Relevance: A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
[Mh] Termos MeSH primário: Cálcio/sangue
Doença da Artéria Coronariana/genética
Predisposição Genética para Doença
Infarto do Miocárdio/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Idoso
Cálcio/efeitos adversos
Doença da Artéria Coronariana/sangue
Suplementos Nutricionais/efeitos adversos
Feminino
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Análise da Randomização Mendeliana
Meia-Idade
Infarto do Miocárdio/sangue
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
SY7Q814VUP (Calcium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.8981


  4 / 468 MEDLINE  
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[PMID]:29198723
[Au] Autor:Richard MA; Huan T; Ligthart S; Gondalia R; Jhun MA; Brody JA; Irvin MR; Marioni R; Shen J; Tsai PC; Montasser ME; Jia Y; Syme C; Salfati EL; Boerwinkle E; Guan W; Mosley TH; Bressler J; Morrison AC; Liu C; Mendelson MM; Uitterlinden AG; van Meurs JB; Franco OH; Zhang G; Li Y; Stewart JD; Bis JC; Psaty BM; Chen YI; Kardia SLR; Zhao W; Turner ST; Absher D; Aslibekyan S; Starr JM; McRae AF; Hou L; Just AC; Schwartz JD; Vokonas PS; Menni C; Spector TD; Shuldiner A; Damcott CM; Rotter JI; Palmas W; Liu Y; Paus T; Horvath S; BIOS Consortium
[Ad] Endereço:Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: melissa.a.lee@uth.tmc.edu.
[Ti] Título:DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
[So] Source:Am J Hum Genet;101(6):888-902, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10 ; replication: N = 7,182, p < 1.6 × 10 ). The replicated methylation sites are heritable (h > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
[Mh] Termos MeSH primário: Pressão Sanguínea/genética
Metilação de DNA/genética
Proteínas do Tecido Nervoso/genética
Tetraspaninas/genética
[Mh] Termos MeSH secundário: Idoso
Ilhas de CpG/genética
Estudos Transversais
Epigênese Genética/genética
Variação Genética/genética
Estudo de Associação Genômica Ampla
Seres Humanos
Análise da Randomização Mendeliana
Meia-Idade
Locos de Características Quantitativas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Nerve Tissue Proteins); 0 (TSPAN2 protein, human); 0 (Tetraspanins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


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[PMID]:28453778
[Au] Autor:Caramaschi D; Sharp GC; Nohr EA; Berryman K; Lewis SJ; Davey Smith G; Relton CL
[Ad] Endereço:Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine.
[Ti] Título:Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment: a two-step Mendelian randomization study.
[So] Source:Hum Mol Genet;26(15):3001-3013, 2017 08 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.
[Mh] Termos MeSH primário: Inteligência/efeitos dos fármacos
Efeitos Tardios da Exposição Pré-Natal/genética
Vitamina B 12/metabolismo
[Mh] Termos MeSH secundário: Adulto
Criança
Cognição/efeitos dos fármacos
Metilação de DNA/genética
Metilação de DNA/fisiologia
Epigênese Genética/genética
Família
Feminino
Sangue Fetal/metabolismo
Genótipo
Seres Humanos
Testes de Inteligência
Estudos Longitudinais
Masculino
Análise da Randomização Mendeliana
Gravidez
Efeitos Tardios da Exposição Pré-Natal/metabolismo
Distribuição Aleatória
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
P6YC3EG204 (Vitamin B 12)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx164


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[PMID]:29212772
[Au] Autor:Larsson SC; Traylor M; Malik R; Dichgans M; Burgess S; Markus HS; CoSTREAM Consortium, on behalf of the International Genomics of Alzheimer's Project
[Ad] Endereço:Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden susanna.larsson@ki.se.
[Ti] Título:Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis.
[So] Source:BMJ;359:j5375, 2017 12 06.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease. DESIGN: Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables. SETTING: International Genomics of Alzheimer's Project. PARTICIPANTS: 17 008 cases of Alzheimer's disease and 37 154 controls. MAIN OUTCOME MEASURES: Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis. RESULTS: This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer's. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10 ) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10 ) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer's (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer's and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer's. Genetically predicted alcohol consumption, serum folate, serum vitamin B , homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer's disease. CONCLUSION: These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer's disease.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Análise da Randomização Mendeliana
[Mh] Termos MeSH secundário: Doença de Alzheimer/etiologia
Dieta
Escolaridade
Predisposição Genética para Doença
Seres Humanos
Estilo de Vida
Razão de Chances
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.j5375


  7 / 468 MEDLINE  
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[PMID]:27778410
[Au] Autor:Sookoian S; Flichman D; Castaño GO; Pirola CJ
[Ad] Endereço:Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
[Ti] Título:Mendelian randomisation suggests no beneficial effect of moderate alcohol consumption on the severity of nonalcoholic fatty liver disease.
[So] Source:Aliment Pharmacol Ther;44(11-12):1224-1234, 2016 12.
[Is] ISSN:1365-2036
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Previous epidemiological studies suggest that patients diagnosed with nonalcoholic fatty liver disease (NAFLD) who drink light to moderate amounts of alcohol (up to ~30 g per day) have less severe histological lesions compared with nondrinkers. However, while the cross-sectional nature of current evidence precludes assessment of causality, cumulative lifetime-exposure of moderate alcohol consumption on histological outcomes has never been evaluated. AIM: To overcome these limitations, a Mendelian randomisation study was performed using a validated genetic variant (rs1229984 A;G) in the alcohol dehydrogenase (ADH1B) gene as a proxy of long-term alcohol exposure. METHODS: We first assessed whether the instrumental variant (rs1229984) was associated with the amount of alcohol consumption in our cohort. We further explored the association between the variant and histological outcomes; a sample of 466 individuals, including 266 patients with NAFLD confirmed by liver biopsy, was studied. RESULTS: We found that carriers of the A-allele consumed significantly lower amounts of alcohol compared with noncarriers (2.3 ± 5.3 vs. 8.18 ± 21 g per day, mean ± s.d., P = 0.03). The analysis of association with the disease severity showed that carriers of the A-allele had lower degree of histological steatosis (1.76 ± 0.83 vs. 2.19 ± 0.78, P = 0.03) and lower scores of lobular inflammation (0.54 ± 0.65 vs. 0.95 ± 0.92, P = 0.02) and NAFLD-Activity Score (2.9 ± 1.4 vs. 3.7 ± 1.4, P = 0.015) compared with noncarriers. CONCLUSION: Mendelian randomisation analysis suggests no beneficial effect of moderate alcohol consumption on NAFLD disease severity.
[Mh] Termos MeSH primário: Álcool Desidrogenase/genética
Consumo de Bebidas Alcoólicas/genética
Hepatopatia Gordurosa não Alcoólica/genética
Hepatopatia Gordurosa não Alcoólica/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Alelos
Biópsia
Feminino
Variação Genética
Seres Humanos
Masculino
Análise da Randomização Mendeliana
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 1.1.1.1 (Alcohol Dehydrogenase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1111/apt.13828


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[PMID]:29089348
[Au] Autor:Dimitrakopoulou VI; Tsilidis KK; Haycock PC; Dimou NL; Al-Dabhani K; Martin RM; Lewis SJ; Gunter MJ; Mondul A; Shui IM; Theodoratou E; Nimptsch K; Lindström S; Albanes D; Kühn T; Key TJ; Travis RC; Vimaleswaran KS; Kraft P; Pierce BL; Schildkraut JM; GECCO Consortium; PRACTICAL Consortium; GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO)
[Ad] Endereço:Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.
[Ti] Título:Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study.
[So] Source:BMJ;359:j4761, 2017 Oct 31.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. Mendelian randomisation study. Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform). 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls. Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations. The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined. There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated. There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.
[Mh] Termos MeSH primário: Neoplasias/sangue
Vitamina D/análogos & derivados
[Mh] Termos MeSH secundário: Neoplasias da Mama/sangue
Neoplasias da Mama/epidemiologia
Neoplasias da Mama/genética
Estudos de Casos e Controles
Neoplasias Colorretais/sangue
Neoplasias Colorretais/epidemiologia
Neoplasias Colorretais/genética
Feminino
Predisposição Genética para Doença
Variação Genética
Estudo de Associação Genômica Ampla
Seres Humanos
Incidência
Neoplasias Pulmonares/sangue
Neoplasias Pulmonares/epidemiologia
Neoplasias Pulmonares/genética
Masculino
Análise da Randomização Mendeliana
Neoplasias/epidemiologia
Neoplasias/genética
Neuroblastoma/sangue
Neuroblastoma/epidemiologia
Neuroblastoma/genética
Neoplasias Ovarianas/sangue
Neoplasias Ovarianas/epidemiologia
Neoplasias Ovarianas/genética
Neoplasias Pancreáticas/sangue
Neoplasias Pancreáticas/epidemiologia
Neoplasias Pancreáticas/genética
Polimorfismo de Nucleotídeo Único
Neoplasias da Próstata/sangue
Neoplasias da Próstata/epidemiologia
Neoplasias da Próstata/genética
Medição de Risco/métodos
Vitamina D/sangue
Deficiência de Vitamina D/sangue
Deficiência de Vitamina D/epidemiologia
Deficiência de Vitamina D/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
1406-16-2 (Vitamin D); 64719-49-9 (25-hydroxyvitamin D)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171102
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.j4761


  9 / 468 MEDLINE  
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[PMID]:28985495
[Au] Autor:Richardson TG; Zheng J; Davey Smith G; Timpson NJ; Gaunt TR; Relton CL; Hemani G
[Ad] Endereço:MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Electronic address: tom.g.richardson@bristol.ac.uk.
[Ti] Título:Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.
[So] Source:Am J Hum Genet;101(4):590-602, 2017 Oct 05.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.
[Mh] Termos MeSH primário: Doenças Cardiovasculares/genética
Ilhas de CpG
Metilação de DNA
Análise da Randomização Mendeliana/métodos
Polimorfismo de Nucleotídeo Único
Locos de Características Quantitativas
[Mh] Termos MeSH secundário: Adenilil Ciclases/genética
Adiponectina/genética
Doenças Cardiovasculares/epidemiologia
Doenças Cardiovasculares/patologia
Criança
Estudos de Coortes
Feminino
Regulação da Expressão Gênica
Genoma Humano
Estudo de Associação Genômica Ampla/métodos
Seres Humanos
Fenótipo
Gravidez
Fatores de Risco
Reino Unido/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ADIPOQ protein, human); 0 (Adiponectin); EC 4.6.1.1 (Adenylyl Cyclases); EC 4.6.1.1 (adenylate cyclase 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


  10 / 468 MEDLINE  
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[PMID]:28981501
[Au] Autor:Paternoster L; Tilling K; Davey Smith G
[Ad] Endereço:Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
[Ti] Título:Genetic epidemiology and Mendelian randomization for informing disease therapeutics: Conceptual and methodological challenges.
[So] Source:PLoS Genet;13(10):e1006944, 2017 Oct.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets, but this has yet to be realized at a level reflecting expectation. One reason for this, we suggest, is that GWAS, to date, have generally not focused on phenotypes that directly relate to the progression of disease and thus speak to disease treatment.
[Mh] Termos MeSH primário: Doença das Coronárias/genética
Doenças Genéticas Inatas/genética
Estudo de Associação Genômica Ampla
Análise da Randomização Mendeliana
[Mh] Termos MeSH secundário: Doença das Coronárias/epidemiologia
Doença das Coronárias/terapia
Progressão da Doença
Doenças Genéticas Inatas/epidemiologia
Doenças Genéticas Inatas/patologia
Doenças Genéticas Inatas/terapia
Predisposição Genética para Doença
Seres Humanos
Fenótipo
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171022
[Lr] Data última revisão:
171022
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006944



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