A recent meta-analysis showed that a Mediterranean style diet may protect against cardiovascular diseases (CVD). Studies on disease-specific associations are limited. We evaluated the Mediterranean ...Diet Score (MDS) in relation to incidence of total and specific CVDs.
The EPIC-NL Study is a cohort of 40,011 men and women aged 20-70 years, examined between 1993 and 1997, with 10-15 years of follow-up. Diet was assessed with a validated food frequency questionnaire and the MDS was based on the daily intakes of vegetables, fruits, legumes and nuts, grains, fish, fatty acids, meat, dairy, and alcohol. Cardiovascular morbidity and mortality were ascertained through linkage with national registries. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for age, sex, cohort, smoking, physical activity, total energy intake, and educational level.
In 34,708 participants free of CVD at baseline, 4881 CVD events occurred, and 487 persons died from CVD. A two unit increment in MDS (range 0-9) was inversely associated with fatal CVD (HR: 0.78; 95%CI: 0.69-0.88), total CVD (HR: 0.95 (0.91-0.98)), myocardial infarction (HR: 0.86 (0.79-0.93)), stroke (HR: 0.88 (0.78-1.00)), and pulmonary embolism (HR: 0.74 (0.59-0.92)). The MDS was not related to incident angina pectoris, transient ischemic attack and peripheral arterial disease.
Better adherence to a Mediterranean style diet was more strongly associated with fatal CVD than with total CVD. Disease specific associations were strongest for incident myocardial infarction, stroke and pulmonary embolism.
IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C)–lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as ...proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. OBJECTIVE: To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. EXPOSURES: Low-density lipoprotein cholesterol–lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for type 2 diabetes and coronary artery disease. RESULTS: Low-density lipoprotein cholesterol–lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L 38.7-mg/dL reduction in LDL-C of 0.61 95% CI, 0.42-0.88; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 95% CI, 1.70-3.43; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. CONCLUSIONS AND RELEVANCE: In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.
Background
The contribution of sufficient sleep duration to lower CVD risk in addition to sufficient physical activity, a healthy diet, (moderate) alcohol consumption, and non-smoking has not been ...investigated yet.
Design
The MORGEN study is a prospective cohort study including 8128 men and 9759 women aged 20–65 years, free of CVD at baseline.
Methods
Sufficient physical activity (≥3.5 h/week cycling or sports), a healthy diet (Mediterranean Diet Score ≥5), (moderate) alcohol consumption (≥1 beverage/month), non-smoking, and sufficient sleep duration (≥7 hours) were assessed by self-administered questionnaires between 1994 and 1997. Cardiovascular morbidity and mortality were ascertained through linkage with national registers. Hazard ratios and preventable proportions were calculated adjusted for age, sex, and educational level.
Results
During 10–14 years of follow up, 607 composite CVD events (fatal CVD, nonfatal myocardial infarction and stroke) occurred, of which 129 were fatal. Those with the four traditional healthy lifestyle factors had a 57% lower risk of composite CVD (HR 0.43, 95% CI 0.31–0.59) and a 67% lower risk of fatal CVD (HR 0.33, 95% CI 0.16–0.68) compared with those with none or one healthy lifestyle factor. Sleeping sufficiently in addition to the four traditional lifestyle factors resulted in a 65% lower risk of composite CVD (HR 0.35, 95% CI 0.23–0.52), and an 83% lower risk of fatal CVD (HR 0.17, 95% CI 0.07–0.43).
Conclusions
Sufficient sleep and adherence to all four traditional healthy lifestyle factors was associated with lower CVD risk. When sufficient sleep duration was added to the traditional lifestyle factors, the risk of CVD was further reduced.
We studied sleep duration and sleep quality in relation to cardiovascular disease (CVD) incidence.
Dutch population-based cohort study.
20,432 men and women aged 20-65 and with no history of CVD.
...N/A.
Sleep duration and sleep quality were assessed by a self-administered questionnaire. Morbidity data, vital status, and causes of death were obtained through linkage with several national registries. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards models.
During 10-15 years of follow-up, 1,486 CVD and 1,148 coronary heart disease (CHD) events occurred. Short sleepers (≤ 6 h) had a 15% higher risk of total CVD (HR: 1.15; 95%CI: 1.00-1.32) and a 23% higher risk of CHD (HR: 1.23 1.04-1.45) compared to normal sleepers (7 h) after adjustment for all confounders. Additional adjustment for intermediate biological risk factors attenuated these relative risks to 1.11 (0.97-1.27) for total CVD and to 1.19 (1.00-1.40) for CHD. Short sleepers with poor sleep quality had a 63% higher risk of CVD (HR: 1.63 1.21-2.19) and a 79% higher risk of CHD incidence (HR: 1.79 1.24-2.58) compared to normal sleepers with good sleep quality, after adjustments for all confounders. We observed no associations between long sleep duration (≥ 9 h) and CVD or CHD incidence.
Short sleepers, especially those with poor sleep quality, have an increased risk of total CVD and CHD incidence. Future investigations should not only focus on sleep duration, but should also take sleep quality into account.
IMPORTANCE: Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes. OBJECTIVE: To investigate the association between time spent cycling and ...all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020. EXPOSURES: The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination. MAIN OUTCOMES AND MEASURES: The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors. RESULTS: Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality. CONCLUSION AND RELEVANCE: In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.
OBJECTIVE: To test the hypothesis that type 2 diabetes is associated with greater decline in cognitive function in middle-aged individuals. RESEARCH DESIGN AND METHODS: In the Dutch prospective ...Doetinchem Cohort Study, cognitive functioning was measured twice within a 5-year time interval in 2,613 men and women. Participants were aged 43-70 years at baseline (1995-2002), and no one had a history of stroke. Change in scores on global cognitive function as well as on specific cognitive function domains (memory, speed of cognitive processes, and cognitive flexibility) were compared for respondents with and without type 2 diabetes (verified by the general practitioner or random plasma glucose levels ≥11.1 mmol/l). RESULTS: At the 5-year follow-up, the decline in global cognitive function in diabetic patients was 2.6 times greater than that in individuals without diabetes. For individuals aged ≥60 years, patients with incident and prevalent diabetes showed a 2.5 and 3.6 times greater decline, respectively, in cognitive flexibility than individuals without diabetes. For most cognitive domains, the magnitude of cognitive decline in patients with incident diabetes was intermediate between that of individuals without diabetes and that of patients with diabetes at baseline. CONCLUSIONS: Middle-aged individuals with type 2 diabetes showed a greater decline in cognitive function than middle-aged individuals without diabetes.
Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically ...predicted plasma vitamin C with type 2 diabetes.
We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.
We identified 11 genomic regions associated with plasma vitamin C (
< 5 × 10
), with the strongest signal at
, and 10 novel genetic loci including
,
,
,
,
,
,
,
,
, and
. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding
variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).
These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
Aims/hypothesis
Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor ...prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts.
Methods
We conducted a meta-analysis of EWASs in blood collected 7–10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK).
Results
The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (
p
values <1.1 × 10
−7
). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and
p
values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA
1c
) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation.
Conclusions/interpretation
By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.
Graphical abstract
Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.
Plasma ...phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation SD 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.
These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.
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