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1.
Int J Obes (Lond) ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388097

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development. METHODS: We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals. RESULTS: We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10-9) and substantia nigra (p = 6.8 × 10-7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions. CONCLUSIONS: Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

2.
Diabetologia ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31396661

RESUMO

AIMS/HYPOTHESIS: Diet is one of the main lifestyle-related factors that can modulate the inflammatory process. Surprisingly the dietary inflammatory index (DII) has been little investigated in relation to type 2 diabetes, and the role of BMI in this relationship is not well established. We studied this association and the role of BMI in the inflammatory process in a large population-based observational study. METHODS: A total of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort study were followed for 20 years. Incident type 2 diabetes cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases, and 3292 incident cases were validated. The DII was derived from a validated food frequency questionnaire. Multivariable Cox regression models estimated HRs and 95% CIs between DII and incident type 2 diabetes. Interactions were tested between DII and BMI on incident type 2 diabetes and a mediation analysis of BMI was performed. RESULTS: Higher DII scores, corresponding to a higher anti-inflammatory potential of the diet, were associated with a lower risk of type 2 diabetes. Compared with the 1st quintile group, women from the 2nd quintile group (HR 0.85 [95% CI 0.77, 0.94]) up to the 5th quintile group (HR 0.77 [95% CI 0.69, 0.85]) had a lower risk of type 2 diabetes before adjustment for BMI. There was an interaction between DII and BMI on type 2 diabetes risk (pInteraction < 0.0001). The overall association was partly mediated by BMI (58%). CONCLUSIONS/INTERPRETATION: Our findings suggest that a higher anti-inflammatory potential of the diet is associated with a lower risk of type 2 diabetes, and the association may be mediated by BMI. These results may improve our understanding of the mechanisms underlying the role of diet-related anti-inflammation in the pathogenesis of type 2 diabetes in women. Further studies are warranted to validate our results and evaluate whether the results are similar in men.

3.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

5.
Diabetologia ; 62(5): 874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30899968

RESUMO

The affiliation details for Geltrude Mingrone are corrected below.

6.
Eur J Endocrinol ; 180(4): 257-263, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840582

RESUMO

Hypothesis Previous work suggested no or inconsistent associations between components of work-related stress and type 2 diabetes risk, but suggested sex-specific differences should be further investigated, as women potentially had higher risks. Methods We analyzed data from 73 517 women, mostly teachers, from the E3N cohort study followed for 22 years (1992-2014), to study the association between mentally tiring work, used as a proxy of job demands, and type 2 diabetes risk. Univariate and multivariable Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Results A total of 4187 incident cases of type 2 diabetes cases were observed. There was a higher type 2 diabetes risk for women with a 'Very mentally tiring work' when compared to women with 'Little or not mentally tiring work' (HR = 1.21 (1.09-1.35)). This association was independent of unhealthy lifestyle and traditional metabolic factors. An interaction between mentally tiring work and BMI was detected (P < 0.0001), with a stronger association being observed in non-overweight women, HR = 1.26 (1.08-1.47) vs HR = 1.14 (0.98, 1.32), in overweight women. Conclusions We observed an increased risk of type 2 diabetes associated with mentally tiring work, used as a proxy of job demands. These observational results suggest the importance of taking into consideration the potential long-term metabolic impact of work-related stress for women working in a demanding environment. Increased support for such women should be investigated in intervention studies.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Emprego/psicologia , Fadiga Mental/complicações , Estresse Ocupacional/psicologia , Estresse Psicológico/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Coortes , Feminino , Seguimentos , França/epidemiologia , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Professores Escolares/psicologia
7.
Prev Med ; 123: 208-216, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30851294

RESUMO

We aimed to determine whether adherence to the Australian dietary guidelines and an index of healthy behavior was associated with a lower risk of type 2 diabetes (T2D) and to provide estimates of the proportion of preventable cases. Participants of the AusDiab cohort study were followed for 12 years (n = 6242), starting from May 1999, during which T2D cases were identified. The associations between T2D risk and a score of adherence to the dietary guidelines, its components, and a score of adherence to an index of healthy behaviors, (which included smoking, recreational physical activity, waist circumference and adherence to the dietary guidelines), were estimated using Cox proportional hazards ratios (HR) and 95% confidence intervals. The proportion of preventable cases was estimated using the population attributable fraction (PAF). Strong adherence to the dietary guidelines was not associated with T2D risk (HR = 0.64 [95% CI 0.39-1.06]), unless moderate alcohol consumption was considered as beneficial instead of no alcohol consumption (HR = 0.59 [0.36-0.96]). However, strong adherence to the guidelines regarding fruit and dairy intake were both associated with decreased risk of T2D (HR = 0.68 [0.51-0.91]; 0.56 [0.38-0.84], respectively) and could have prevented 23-37% of cases (PAF = 23.3% [7.3-38.2]; 37.1% [14.6-56.0], respectively). Strong adherence to the index of healthy behaviors was associated with decreased risk of T2D (HR = 0.30 [0.17-0.51]) and estimated to prevent almost 60% of T2D (PAF = 59.4% [34.3-76.6]). More than half of T2D cases could be preventable in Australia through modifying health behavior. These results could serve as a basis for prevention programs based on lifestyle modification.

8.
Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226

RESUMO

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
11.
JAMA Neurol ; 76(3): 257-263, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30556831

RESUMO

Importance: Little is known about the associations between migraine and type 2 diabetes and the temporality of the association between these 2 diseases. Objective: To evaluate the association between migraine and type 2 diabetes incidence as well as the evolution of the prevalence of active migraine before and after type 2 diabetes diagnosis. Design, Setting, and Participants: We used data from the E3N cohort study, a French prospective population-based study initiated in 1990 on a cohort of women born between 1925 and 1950. The E3N study participants are insured by a health insurance plan that mostly covers teachers. From the eligible women in the E3N study, we included those who completed the 2002 follow-up questionnaire with information available on migraine. We then excluded prevalent cases of type 2 diabetes, leaving a final sample of women who were followed up between 2004 and 2014. All potential occurrences of type 2 diabetes were identified through a drug reimbursement database. Statistical analyses were performed in March 2018. Exposures: Self-reported migraine occurrence. Main Outcomes and Measures: Pharmacologically treated type 2 diabetes. Results: From the 98 995 women in the study, 76 403 women completed the 2002 follow-up survey. Of these, 2156 were excluded because they had type 2 diabetes, leaving 74 247 women. Participants had a mean (SD) age of 61 (6) years at baseline, and all were free of type 2 diabetes. During 10 years of follow-up, 2372 incident type 2 diabetes cases occurred. A lower risk of type 2 diabetes was observed for women with active migraine compared with women with no migraine history (univariate hazard ratio, 0.80 [95% CI, 0.67-0.96], multivariable-adjusted hazard ratio, 0.70 [95% CI, 0.58-0.85]). We also observed a linear decrease in active migraine prevalence from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) during the 24 years prior to diabetes diagnosis, after adjustment for potential type 2 diabetes risk factors. A plateau of migraine prevalence around 11% was then observed for 22 years after diagnosis. Conclusions and Relevance: We observed a lower risk of developing type 2 diabetes for women with active migraine and a decrease in active migraine prevalence prior to diabetes diagnosis. Further targeted research should focus on understanding the mechanisms involved in explaining these findings.

12.
Chronic Illn ; : 1742395318801934, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282463

RESUMO

Objectives Identification of characteristics associated with a negative experience with type 2 diabetes may help to develop novel intervention to improve the outlook of people with the disease. Our aim was to identify determinants of a self-reported concerned vision about the future when living with type 2 diabetes. Methods In 2630 women with type 2 diabetes from the E3N-AfterDiab study, we used multivariable logistic regression models to derive odds-ratios and 95% confidence intervals. Results Women with elevated HbA1c levels (OR = 2.42 (1.67-3.49) for ≥7.2% when compared to <6.2%), or treated with injected glucose lowering treatments (OR = 1.37 [1.05-1.81]) had a higher risk of a concerned vision of the future. Age and obesity were associated with a decreased risk. Hypertension, duration of diabetes, smoking, fasting glucose levels, and years of education were not associated with a concerned vision of the future. Discussion Our findings highlight the importance of both glycemic control and the type of treatment on the perception of the future when living with type 2 diabetes. Subgroups of patients based on these characteristics may receive a specific attention from healthcare professionals to address potential concerns related with diabetes management or the fear of complications.

13.
Clin Nutr ; 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30193875

RESUMO

BACKGROUND: Iodine is an essential micronutrient needed for the production of thyroid hormones. Consequently, iodine insufficient and excessive intakes are associated with thyroid disorders. Despite the increase in diabetes prevalence worldwide and the close relationship between thyroid function and the risk of diabetes, the relationship between iodine intake and diabetes has been overlooked. The objective of the present study is to investigate the link between iodine intake and the risk of type 2 diabetes. METHODS: Cox proportional hazards regression models adjusted on potential confounders were used to calculate the hazard ratios and 95% confidence intervals for the associations between dietary iodine intake and type 2 diabetes risk among 71,264 women of the E3N-EPIC cohort. RESULTS: The average iodine intake in the study population was 155.6 µg/day (±47.1 µg/day). After adjusting for the main risk factors for diabetes, for hypo/hyperthyroidism, as well as for phosphorus intakes and consumption of dairy products and seafood, the hazard ratios (95% CI) for type 2 diabetes of women in the 4th (160.7-190.5 µg/day) and 5th (190.6-596.8 µg/day) quintiles groups of iodine intake were 1.27 (1.10-1.47) and 1.28 (1.07-1.53), respectively, compared to women with iodine intake below the 1st quintile (29.3-116.9 µg/day). CONCLUSION: This is the first study to investigate the relationship between dietary iodine intake and the risk of developing type 2 diabetes. More studies are warranted to further investigate the health effects of chronic high iodine intake, and in particular to investigate the biological mechanisms that underlie the association between iodine intake and type 2 diabetes.

14.
J Diabetes ; 2018 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-30098121

RESUMO

BACKGROUND: Although many type 2 diabetes mellitus (T2DM) risk factors have been identified, little is known regarding their contributions to the diabetes burden at the population level. METHODS: The study included 72 655 French women from the Etude Epidemiologique de Femmes de la Mutuelle Générale de l'Education Nationale (E3N) prospective cohort followed between 1993 and 2011. Cox multivariable models including the main T2DM risk factors (metabolic, dietary, clinical, socioeconomic and hormonal) and a healthy lifestyle index combining five characteristics (smoking, body mass index [BMI], alcohol consumption, fruit and vegetable consumption, and physical activity) were used to estimate hazard ratios and population attributable fractions (PAFs) for T2DM. RESULTS: In multivariate models, factors with the strongest effect on T2DM risk were, in decreasing order, BMI ≥ 30 kg/m2 (PAF = 43%; 95% confidence interval [CI] 37-47), high adherence to a Western dietary pattern (PAF = 30%; 95% CI 20-40), hypertension (PAF = 26%; 95% CI 20-32), an acidogenic diet (PAF = 24%; 95% CI 16-32), a family history of diabetes (PAF = 20%; 95% CI 17-22), and, with a negative correlation, moderate alcohol consumption (PAF-19%; 95% CI -34, -4). The PAF for an unhealthy lifestyle was 57% (95% CI 50-63). CONCLUSIONS: We have been able to sort out and quantify the effect of various dietary and biological T2DM risk factors simultaneously in a single population, and to highlight the importance of a healthy lifestyle for primary prevention: more than half the T2DM cases could have been prevented through a healthier lifestyle.

15.
JCI Insight ; 3(13)2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997293

RESUMO

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition.

16.
Front Genet ; 9: 210, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963075

RESUMO

In observational cohorts, longitudinal data are collected with repeated measurements at predetermined time points for many biomarkers, along with other variables measured at baseline. In these cohorts, time until a certain event of interest occurs is reported and very often, a relationship will be observed between some biomarker repeatedly measured over time and that event. Joint models were designed to efficiently estimate statistical parameters describing this relationship by combining a mixed model for the longitudinal biomarker trajectory and a survival model for the time until occurrence of the event, using a set of random effects to account for the relationship between the two types of data. In this paper, we discuss the implementation of joint models in genetic association studies. First, we check model consistency based on different simulation scenarios, by varying sample sizes, minor allele frequencies and number of repeated measurements. Second, using genotypes assayed with the Metabochip DNA arrays (Illumina) from about 4,500 individuals recruited in the French cohort D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome), we assess the feasibility of implementing the joint modelling approach in a real high-throughput genomic dataset. An alternative model approximating the joint model, called the Two-Step approach (TS), is also presented. Although the joint model shows more precise and less biased estimators than its alternative counterpart, the TS approach results in much reduced computational times, and could thus be used for testing millions of SNPs at the genome-wide scale.

17.
Diabetes Care ; 41(8): 1740-1748, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29853473

RESUMO

OBJECTIVE: Glucose measurements during an oral glucose tolerance test (OGTT) are useful in predicting diabetes and its complications. However, knowledge of the pathophysiology underlying differences in glucose curve shapes is sparse. We examined the pathophysiological characteristics that create different glucose curve patterns and studied their stability and reproducibility over 3 years of follow-up. RESEARCH DESIGN AND METHODS: We analyzed data from participants without diabetes from the observational cohort from the European Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and Cardiovascular Disease study; participants had a five-time point OGTT at baseline (n = 1,443) and after 3 years (n = 1,045). Measures of insulin sensitivity and secretion were assessed at baseline with a euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance test. Heterogeneous glucose response patterns during the OGTT were identified using latent class trajectory analysis at baseline and at follow-up. Transitions between classes were analyzed with multinomial logistic regression models. RESULTS: We identified four different glucose response patterns, which differed with regard to insulin sensitivity and acute insulin response, obesity, and plasma levels of lipids and inflammatory markers. Some of these associations were confirmed prospectively. Time to glucose peak was driven mainly by insulin sensitivity, whereas glucose peak size was related to both insulin sensitivity and secretion. The glucose patterns identified at follow-up were similar to those at baseline, suggesting that the latent class method is robust. We integrated our classification model into an easy-to-use online application that facilitates the assessment of glucose curve patterns for other studies. CONCLUSIONS: The latent class analysis approach is a pathophysiologically insightful way to classify individuals without diabetes based on their response to glucose during an OGTT.


Assuntos
Glicemia/análise , Glicemia/metabolismo , Resistência à Insulina/fisiologia , Adulto , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Técnica Clamp de Glucose , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Reprodutibilidade dos Testes
18.
BMC Nephrol ; 19(1): 124, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855339

RESUMO

BACKGROUND: People with chronic renal disease are insulin resistant. We hypothesized that in a healthy population, baseline renal function is associated with insulin sensitivity three years later. METHODS: We studied 405 men and 528 women from the European Group for the study of Insulin Resistance - Relationship between Insulin Sensitivity and Cardiovascular disease cohort. Renal function was characterized by the estimated glomerular filtration rate (eGFR) and by the urinary albumin-creatinine ratio (UACR). At baseline only, insulin sensitivity was quantified using a hyperinsulinaemic-euglycaemic clamp; at baseline and three years, we used surrogate measures: the Matsuda insulin sensitivity index (ISI), the HOmeostasis Model Assessment of Insulin Sensitivity (HOMA-IS). Associations between renal function and insulin sensitivity were studied cross-sectionally and longitudinally. RESULTS: In men at baseline, no associations were seen with eGFR, but there was some evidence of a positive association with UACR. In women, all insulin sensitivity indices showed the same negative trend across eGFR classes, albeit not always statistically significant; for UACR, women with values above the limit of detection, had higher clamp measured insulin sensitivity than other women. After three years, in men only, ISI and HOMA-IS showed a U-shaped relation with baseline eGFR; women with eGFR> 105 ml/min/1.73m2 had a significantly higher insulin sensitivity than the reference group (eGFR: 90-105 ml/min/1.73m2). For both men and women, year-3 insulin sensitivity was higher in those with higher baseline UACR. All associations were attenuated after adjusting on significant covariates. CONCLUSIONS: There was no evidence to support our hypothesis that markers of poorer renal function are associated with declining insulin sensitivity in our healthy population.

19.
Lancet ; 391(10129): 1513-1523, 2018 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-29676281

RESUMO

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/mortalidade , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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