Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 161
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Cardiovasc Disord ; 19(1): 240, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664920

RESUMO

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

2.
Diabetes ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506343

RESUMO

Epigenetic changes may contribute substantially to risks of diseases of ageing. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based EPIC-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset to investigate the role of methylation in the aetiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM, and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1 and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs, and found one MVP, cg00574958 at CPT1A, with a possible direct causal role on T2DM. None of the implicated genes was previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

3.
J Nutr ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396627

RESUMO

INTRODUCTION: Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another. OBJECTIVE: The aim of this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992-2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D. RESULTS: Mean ± SD of estimated consumption of SSB was 55 ± 105 g/d. Means ± SDs for the other beverages were as follows: fruit juice, 59 ± 101 g/d; milk, 209 ± 203 g/d; coffee, 381 ± 372 g/d; and tea, 152 ± 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was -12.0 (95% CI: -20.0, -5.0) per 10,000 person-years among adults consuming SSBs ≥250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or -11.0 (95% CI: -20.0, -2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly. CONCLUSIONS: These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations.

4.
BMJ ; 366: l4292, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345923

RESUMO

OBJECTIVE: To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. DESIGN: Individual participant data meta-analysis. DATA SOURCES: Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. REVIEW METHODS: Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. RESULTS: Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. CONCLUSIONS: These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Adulto , Alelos , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
5.
Am J Epidemiol ; 188(6): 991-1012, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155658

RESUMO

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

6.
J Nutr ; 149(6): 1047-1055, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31149710

RESUMO

BACKGROUND: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence. OBJECTIVE: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries. METHODS: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association. RESULTS: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea. CONCLUSIONS: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.

7.
EBioMedicine ; 44: 467-475, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31151930

RESUMO

BACKGROUND: Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored. METHODS: An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue. FINDINGS: We found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways. INTERPRETATION: These data identify a role for miR-196a in regulating human body fat distribution. FUND: This work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1.

8.
Sci Rep ; 9(1): 9386, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253830

RESUMO

Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11-1.34, P-value = 6 × 10-5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05-1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.

9.
Diabetes ; 68(8): 1681-1691, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088856

RESUMO

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

10.
PLoS One ; 14(5): e0217644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31145760

RESUMO

Waist-to-hip ratio (WHR) is a prominent cardiometabolic risk factor that increases cardio-metabolic disease risk independently of BMI and for which multiple genetic loci have been identified. However, WHR is a relatively crude proxy for fat distribution and it does not capture all variation in fat distribution. We here present a study of the role of coding genetic variants on fat mass in 6 distinct regions of the body, based on dual-energy X-ray absorptiometry imaging on more than 17k participants. We find that the missense variant CCDC92S70C, previously associated with WHR, is associated specifically increased leg fat mass and reduced visceral but not subcutaneous central fat. The minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue samples. In addition, we identify two coding variants in SPATA20 and UQCC1 that are associated with arm fat mass. SPATA20K422R is a low-frequency variant with a large effect on arm fat only, and UQCC1R51Q is a common variant reaching significance for arm but showing similar trends in other subcutaneous fat depots. Our findings support the notion that different fat compartments are regulated by distinct genetic factors.

11.
Cell ; 177(3): 597-607.e9, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31002796

RESUMO

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of ß-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward ß-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing ß-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.

12.
Circulation ; 139(25): 2835-2845, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31006335

RESUMO

BACKGROUND: There is uncertainty about the relevance of animal foods to the pathogenesis of ischemic heart disease (IHD). We examined meat, fish, dairy products, and eggs and risk for IHD in the pan-European EPIC cohort (European Prospective Investigation Into Cancer and Nutrition). METHODS: In this prospective study of 409 885 men and women in 9 European countries, diet was assessed with validated questionnaires and calibrated with 24-hour recalls. Lipids and blood pressure were measured in a subsample. During a mean of 12.6 years of follow-up, 7198 participants had a myocardial infarction or died of IHD. The relationships of animal foods with risk were examined with Cox regression with adjustment for other animal foods and relevant covariates. RESULTS: The hazard ratio (HR) for IHD was 1.19 (95% CI, 1.06-1.33) for a 100-g/d increment in intake of red and processed meat, and this remained significant after exclusion of the first 4 years of follow-up (HR, 1.25 [95% CI, 1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR, 0.93 [95% CI, 0.89-0.98] per 100-g/d increment), cheese (HR, 0.92 [95% CI, 0.86-0.98] per 30-g/d increment), and eggs (HR, 0.93 [95% CI, 0.88-0.99] per 20-g/d increment); the associations with yogurt and eggs were attenuated and nonsignificant after exclusion of the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish, or milk. In analyses modeling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese, or eggs was associated with ≈20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-high-density lipoprotein cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-high-density lipoprotein cholesterol. CONCLUSIONS: Risk for IHD was positively associated with consumption of red and processed meat and inversely associated with consumption of yogurt, cheese, and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-high-density lipoprotein cholesterol and for red and processed meat with systolic blood pressure, which could mediate such effects.

13.
Nat Commun ; 10(1): 1060, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837465

RESUMO

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Glicina/sangue , Hiperinsulinismo/genética , Redes e Vias Metabólicas/genética , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glicina/metabolismo , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/epidemiologia , Incidência , Polimorfismo de Nucleotídeo Único
14.
Diabetes Care ; 42(4): 568-575, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30728219

RESUMO

OBJECTIVE: To estimate the causal association between intake of dairy products and incident type 2 diabetes. RESEARCH DESIGN AND METHODS: The analysis included 21,820 European individuals (9,686 diabetes cases) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study. Participants were genotyped, and rs4988235 (LCT-12910C>T), a single nucleotide polymorphism (SNP) for lactase persistence (LP) that enables digestion of dairy sugar, i.e., lactose, was imputed. Baseline dietary intakes were assessed with diet questionnaires. We investigated the associations between imputed SNP dosage for rs4988235 and intake of dairy products and other foods through linear regression. Mendelian randomization (MR) estimates for the milk-diabetes relationship were obtained through a two-stage least squares regression. RESULTS: Each additional LP allele was associated with a higher intake of milk (ß 17.1 g/day, 95% CI 10.6-23.6) and milk beverages (ß 2.8 g/day, 95% CI 1.0-4.5) but not with intake of other dairy products. Other dietary intakes associated with rs4988235 included fruits (ß -7.0 g/day, 95% CI -12.4 to -1.7 per additional LP allele), nonalcoholic beverages (ß -18.0 g/day, 95% CI -34.4 to -1.6), and wine (ß -4.8 g/day, 95% CI -9.1 to -0.6). In instrumental variable analysis, LP-associated milk intake was not associated with diabetes (hazard ratioper 15 g/day 0.99, 95% CI 0.93-1.05). CONCLUSIONS: rs4988235 was associated with milk intake but not with intake of other dairy products. This MR study does not suggest that milk intake is associated with diabetes, which is consistent with previous observational and genetic associations. LP may be associated with intake of other foods as well, but owing to the modest associations, we consider it unlikely that this caused the observed null result.

15.
Int J Epidemiol ; 48(4): 1275-1285, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796459

RESUMO

BACKGROUND: Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors. METHODS: We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders. RESULTS: After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors. CONCLUSIONS: Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.

16.
JAMA ; 320(24): 2553-2563, 2018 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-30575882

RESUMO

Importance: Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown. Objective: To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their association with cardiometabolic risk. Design, Setting, and Participants: Genome-wide association studies (GWAS) for WHR combined data from the UK Biobank cohort and summary statistics from previous GWAS (data collection: 2006-2018). Specific polygenic scores for higher WHR via lower gluteofemoral or via higher abdominal fat distribution were derived using WHR-associated genetic variants showing specific association with hip or waist circumference. Associations of polygenic scores with outcomes were estimated in 3 population-based cohorts, a case-cohort study, and summary statistics from 6 GWAS (data collection: 1991-2018). Exposures: More than 2.4 million common genetic variants (GWAS); polygenic scores for higher WHR (follow-up analyses). Main Outcomes and Measures: BMI-adjusted WHR and unadjusted WHR (GWAS); compartmental fat mass measured by dual-energy x-ray absorptiometry, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting glucose, fasting insulin, type 2 diabetes, and coronary disease risk (follow-up analyses). Results: Among 452 302 UK Biobank participants of European ancestry, the mean (SD) age was 57 (8) years and the mean (SD) WHR was 0.87 (0.09). In genome-wide analyses, 202 independent genetic variants were associated with higher BMI-adjusted WHR (n = 660 648) and unadjusted WHR (n = 663 598). In dual-energy x-ray absorptiometry analyses (n = 18 330), the hip- and waist-specific polygenic scores for higher WHR were specifically associated with lower gluteofemoral and higher abdominal fat, respectively. In follow-up analyses (n = 636 607), both polygenic scores were associated with higher blood pressure and triglyceride levels and higher risk of diabetes (waist-specific score: odds ratio [OR], 1.57 [95% CI, 1.34-1.83], absolute risk increase per 1000 participant-years [ARI], 4.4 [95% CI, 2.7-6.5], P < .001; hip-specific score: OR, 2.54 [95% CI, 2.17-2.96], ARI, 12.0 [95% CI, 9.1-15.3], P < .001) and coronary disease (waist-specific score: OR, 1.60 [95% CI, 1.39-1.84], ARI, 2.3 [95% CI, 1.5-3.3], P < .001; hip-specific score: OR, 1.76 [95% CI, 1.53-2.02], ARI, 3.0 [95% CI, 2.1-4.0], P < .001), per 1-SD increase in BMI-adjusted WHR. Conclusions and Relevance: Distinct genetic mechanisms may be linked to gluteofemoral and abdominal fat distribution that are the basis for the calculation of the WHR. These findings may improve risk assessment and treatment of diabetes and coronary disease.


Assuntos
Gordura Abdominal , Adiposidade/genética , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Variação Genética , Relação Cintura-Quadril , Índice de Massa Corporal , Doenças Cardiovasculares/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
Artigo em Inglês | MEDLINE | ID: mdl-30418614

RESUMO

Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: non-epimeric and epimeric 25(OH)D3 stereoisomers; and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the EPIC-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13562 subcohort members. Plasma vitamin D metabolites were quantified by liquid-chromatography mass-spectrometry. We used multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates combined across countries using random-effects meta-analysis. Results: The mean concentrations (standard deviation) of total 25(OH)D, non-epimeric 25(OH)D3, epimeric 25(OH)D3 and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and non-epimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1-SD=0.81 (95%CI: 0.77, 0.86) for both variables], while epimeric 25(OH)D3 was positively associated: per 1-SD HR=1.16 (1.09, 1.25). There was no statistically significant association with T2D for 25(OH)D2 [per 1-SD HR=0.94 (0.76, 1.18)]. Conclusions: Plasma non-epimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

18.
JAMA Cardiol ; 3(10): 957-966, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30326043

RESUMO

Importance: Pharmacological enhancers of lipoprotein lipase (LPL) are in preclinical or early clinical development for cardiovascular prevention. Studying whether these agents will reduce cardiovascular events or diabetes risk when added to existing lipid-lowering drugs would require large outcome trials. Human genetics studies can help prioritize or deprioritize these resource-demanding endeavors. Objective: To investigate the independent and combined associations of genetically determined differences in LPL-mediated lipolysis and low-density lipoprotein cholesterol (LDL-C) metabolism with risk of coronary disease and diabetes. Design, Setting, and Participants: In this genetic association study, individual-level genetic data from 392 220 participants from 2 population-based cohort studies and 1 case-cohort study conducted in Europe were included. Data were collected from January 1991 to July 2018, and data were analyzed from July 2014 to July 2018. Exposures: Six conditionally independent triglyceride-lowering alleles in LPL, the p.Glu40Lys variant in ANGPTL4, rare loss-of-function variants in ANGPTL3, and LDL-C-lowering polymorphisms at 58 independent genomic regions, including HMGCR, NPC1L1, and PCSK9. Main Outcomes and Measures: Odds ratio for coronary artery disease and type 2 diabetes. Results: Of the 392 220 participants included, 211 915 (54.0%) were female, and the mean (SD) age was 57 (8) years. Triglyceride-lowering alleles in LPL were associated with protection from coronary disease (approximately 40% lower odds per SD of genetically lower triglycerides) and type 2 diabetes (approximately 30% lower odds) in people above or below the median of the population distribution of LDL-C-lowering alleles at 58 independent genomic regions, HMGCR, NPC1L1, or PCSK9. Associations with lower risk were consistent in quintiles of the distribution of LDL-C-lowering alleles and 2 × 2 factorial genetic analyses. The 40Lys variant in ANGPTL4 was associated with protection from coronary disease and type 2 diabetes in groups with genetically higher or lower LDL-C. For a genetic difference of 0.23 SDs in LDL-C, ANGPTL3 loss-of-function variants, which also have beneficial associations with LPL lipolysis, were associated with greater protection against coronary disease than other LDL-C-lowering genetic mechanisms (ANGPTL3 loss-of-function variants: odds ratio, 0.66; 95% CI, 0.52-0.83; 58 LDL-C-lowering variants: odds ratio, 0.90; 95% CI, 0.89-0.91; P for heterogeneity = .009). Conclusions and Relevance: Triglyceride-lowering alleles in the LPL pathway are associated with lower risk of coronary disease and type 2 diabetes independently of LDL-C-lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C-lowering therapy.

19.
Sci Signal ; 11(545)2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154102

RESUMO

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT2, a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous ß-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk. Computational variant impact prediction by in silico evolutionary lineage analysis strongly correlated with the measured phenotypic effect of each variant, providing a predictive tool for future studies on GPCR variants. Together, this large-scale functional study provides an operational framework for the postgenomic analysis of the multiple GPCR variants present in the human population. The association of T2D risk with signaling pathway-specific defects opens avenues for pathway-specific personalized therapeutic intervention and reveals the potential relevance of MT2 function during the day, when melatonin is undetectable, but spontaneous activity of the receptor occurs.

20.
Nat Genet ; 50(8): 1112-1121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038396

RESUMO

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA