[Show abstract][Hide abstract] ABSTRACT: Background/aims:
Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.
The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD.
A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up.
This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.
[Show abstract][Hide abstract] ABSTRACT: IntroductionSpecific coffee subtypes and tea may impact risk of pre- and post-menopausal breast cancer differently. We investigated the association between coffee (total, caffeinated, decaffeinated) and tea intake and risk of breast cancer.MethodsA total of 335,060 women participating in the European Prospective Investigation into Nutrition and Cancer (EPIC) Study, completed a dietary questionnaire from 1992 to 2000, and were followed-up until 2010 for incidence of breast cancer. Hazard ratios (HR) of breast cancer by country-specific, as well as cohort-wide categories of beverage intake were estimated.ResultsDuring an average follow-up of 11 years, 1064 premenopausal, and 9134 postmenopausal breast cancers were diagnosed. Caffeinated coffee intake was associated with lower risk of postmenopausal breast cancer: adjusted HR¿=¿0.90, 95% confidence interval (CI): 0.82 to 0.98, for high versus low consumption; P trend¿=¿0.029. While there was no significant effect modification by hormone receptor status (P¿=¿0.711), linear trend for lower risk of breast cancer with increasing caffeinated coffee intake was clearest for estrogen and progesterone receptor negative (ER-PR-), postmenopausal breast cancer (P¿=¿0.008). For every 100 ml increase in caffeinated coffee intake, the risk of ER-PR- breast cancer was lower by 4% (adjusted HR: 0.96, 95% CI: 0.93 to 1.00). Non-consumers of decaffeinated coffee had lower risk of postmenopausal breast cancer (adjusted HR¿=¿0.89; 95% CI: 0.80 to 0.99) compared to low consumers, without evidence of dose¿response relationship (P trend¿=¿0.128). Exclusive decaffeinated coffee consumption was not related to postmenopausal breast cancer risk, compared to any decaffeinated-low caffeinated intake (adjusted HR¿=¿0.97; 95% CI: 0.82 to 1.14), or to no intake of any coffee (HR: 0.96; 95%: 0.82 to 1.14). Caffeinated and decaffeinated coffee were not associated with premenopausal breast cancer. Tea intake was neither associated with pre- nor post-menopausal breast cancer.Conclusions
Higher caffeinated coffee intake may be associated with lower risk of postmenopausal breast cancer. Decaffeinated coffee intake does not seem to be associated with breast cancer.
Full-text · Article · Jan 2015 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: Fish is a source of important nutrients and may play a role in preventing heart diseases and other health
outcomes. However, studies of overall mortality and causespecific mortality related to fish consumption are inconclusive. We examined the rate of overall mortality, as well as mortality from ischaemic heart disease and cancer in relation to the intake of total fish, lean fish, and fatty fish in a large prospective cohort including ten European countries. More than 500,000 men and women completed a dietary questionnaire in 1992–1999 and were followed up for mortality until the end of 2010. 32,587 persons were reported dead since enrolment. Hazard ratios and their 99 % confidence interval were estimated using Cox proportional hazard regression models. Fish consumption was examined using quintiles based on reported consumption, using moderate fish consumption (third quintile) as reference, and as continuous variables, using ncrements of 10 g/day. All analyses were adjusted for possible confounders. No association was seen for fish consumption and overall or cause-specific mortality for both the categorical and the continuous analyses, but there seemed to be a U-shaped trend (p\0.000) with fatty fish consumption and total mortality and with total fish consumption and cancer mortality (p = 0.046).
Full-text · Article · Nov 2014 · European Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Objective:
The aims of this study were to investigate the association between smoking and incident type 2 diabetes, accounting for a large number of potential confounding factors, and to explore potential effect modifiers and intermediate factors.
Research design and methods:
The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct is a prospective case-cohort study within eight European countries, including 12,403 cases of incident type 2 diabetes and a random subcohort of 16,835 individuals. After exclusion of individuals with missing data, the analyses included 10,327 cases and 13,863 subcohort individuals. Smoking status was used (never, former, current), with never smokers as the reference. Country-specific Prentice-weighted Cox regression models and random-effects meta-analysis were used to estimate hazard ratios (HRs) for type 2 diabetes.
In men, the HRs (95% CI) of type 2 diabetes were 1.40 (1.26, 1.55) for former smokers and 1.43 (1.27, 1.61) for current smokers, independent of age, education, center, physical activity, and alcohol, coffee, and meat consumption. In women, associations were weaker, with HRs (95% CI) of 1.18 (1.07, 1.30) and 1.13 (1.03, 1.25) for former and current smokers, respectively. There was some evidence of effect modification by BMI. The association tended to be slightly stronger in normal weight men compared with those with overall adiposity.
Former and current smoking was associated with a higher risk of incident type 2 diabetes compared with never smoking in men and women, independent of educational level, physical activity, alcohol consumption, and diet. Smoking may be regarded as a modifiable risk factor for type 2 diabetes, and smoking cessation should be encouraged for diabetes prevention.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To investigate whether blood-based biomarkers can improve the prediction of visceral fat volume as measured by magnetic resonance imaging (MRI) and thus be used as proxies of visceral adiposity in large-scale epidemiological studies.
Whole-body MRI was performed to determine overall and regional body compartments in 542 participants aged 48-80 years (52% men) of the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. Anthropometric measures were taken, and clinical chemistry profiles including 15 routine biomarkers were obtained. Furthermore, nine novel biomarkers of visceral fat were assayed in a discovery sample of 100 participants. Multivariable regression models were calculated to assess associations between anthropometric variables, biomarkers, and visceral fat volume.
The proportion of variance in visceral fat volume explained by anthropometric measures was 65.2% in women and 60.8% in men. By using blood-based biomarkers in addition to anthropometric indices, the variance in visceral fat volume explained could be increased by 4.8% in women and 4.0% in men. After backward selection, HbA1c, triglycerides, and adiponectin remained in the final multivariable regression model in women, while in men hsCRP, leukocytes, AST (GOT), GGT, LDL, and adiponectin remained in the final model.
In the present study, blood-based biomarkers moderately improved the prediction of visceral fat volume. This finding suggests that the underestimation of true associations between visceral fat and disease outcomes in epidemiological studies remains critical, even when using comprehensive sets of anthropometric and biomarker variables as proxies of visceral adiposity.
Full-text · Article · Aug 2014 · European Journal of Nutrition
[Show abstract][Hide abstract] ABSTRACT: We hypothesised that consumption of flavanol-containing apple puree would modulate platelet activity and increase nitric oxide metabolite status, and that high flavanol apple puree would exert a greater effect than low flavanol apple puree. 25 subjects consumed 230 g of apple puree containing 25 and 100 mg epicatechin (low and high flavanol apple puree, respectively) and aspirin (75 mg) in random order. Measurements were made at baseline, acutely after treatment (2, 6 and 24 h), and after 14 d of treatment. Low flavanol apple puree significantly attenuated ADP and epinephrine-induced integrin-β3 expression 2 h and 6 h after consumption and ADP and epinephrine-induced P-selectin expression within 2 h of consumption. High flavanol apple puree attenuated epinephrine and ADP-induced integrin-β3 expression after 2 and 6h. ADP and epinephrine-induced integrin-β3 expression was significantly attenuated 2, 6 and 24h after consumption of aspirin, while 14 d aspirin consumption attenuated collagen-induced P-selectin expression only. The plasma total nitric oxide metabolite conc. was significantly increased 6 h after consumption of both low and high flavanol apple purees. In conclusion, consumption of apple purees containing ⩾25 or 100 mg flavanols transiently attenuated ex vivo integrin-β3 and P-selectin expression and increased plasma nitric oxide metabolite conc. in healthy subjects, but the effect was not enhanced for the high flavanol apple puree.
Full-text · Article · Jun 2014 · Archives of Biochemistry and Biophysics
[Show abstract][Hide abstract] ABSTRACT: In epidemiological studies, measures of body fat generally are obtained through anthropometric indices such as the body mass index (BMI), waist (WC), and hip circumferences (HC). Such indices, however, can only provide estimates of a person's true body fat content, overall or by adipose compartment, and may have limited accuracy, especially for the visceral adipose compartment (VAT).
To determine the extent to which different body adipose tissue compartments are adequately predicted by anthropometry, and to identify anthropometric measures alone, or in combination to predict overall adiposity and specific adipose tissue compartments, independently of age and body size (height).
In a sub-study of 1,192 participants of the German EPIC (European Prospective Investigation into Cancer and Nutrition) cohorts, whole-body MRI was performed to determine adipose and muscle tissue compartments. Additional anthropometric measurements of BMI, WC and HC were taken.
After adjusting for age and height, BMI, WC and HC were better predictors of total body volume (TBV), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) than for VAT, coronary adipose tissue (CAT) and skeletal muscle tissue (SMT). In both sexes, BMI was the best predictor for TBV (men: r = 0.72 [0.68-0.76], women: r = 0.80 [0.77-0.83]) and SMT (men: r = 0.52 [0.45-0.57], women: r = 0.48 [0.41-0.54]). WC was the best predictor variable for TAT (r = 0.48 [0.41-0.54]), VAT (r = 0.44 [0.37-0.50]) and CAT (r = 0.34 [0.26-0.41]) (men), and for VAT (r = 0.42 [0.35-0.49]) and CAT (r = 0.29 [0.22-0.37]) (women). BMI was the best predictor for TAT (r = 0.49 [0.43-0.55]) (women). HC was the best predictor for SAT (men (r = 0.39 [0.32-0.45]) and women (r = 0.52 [0.46-0.58])).
Especially the volumes of internal body fat compartments are poorly predicted by anthropometry. A possible implication may be that associations of chronic disease risks with the sizes of internal body fat as measured by BMI, WC and HC may be strongly underestimated.
[Show abstract][Hide abstract] ABSTRACT: Health-beneficial effects of adhering to a healthy Nordic diet index have been suggested. However, it has not been examined to what extent the included dietary components are exclusively related to the Nordic countries or if they are part of other European diets as well, suggesting a broader preventive potential. The present study describes the intake of seven a priori defined healthy food items (apples/pears, berries, cabbages, dark bread, shellfish, fish and root vegetables) across ten countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) and examines their consumption across Europe.
Cross-sectional study. A 24 h dietary recall was administered through a software program containing country-specific recipes. Sex-specific mean food intake was calculated for each centre/country, as well as percentage of overall food groups consumed as healthy Nordic food items. All analyses were weighted by day and season of data collection.
Multi-centre, European study.
Persons (n 36 970) aged 35-74 years, constituting a random sample of 519 978 EPIC participants.
The highest intakes of the included diet components were: cabbages and berries in Central Europe; apples/pears in Southern Europe; dark bread in Norway, Denmark and Greece; fish in Southern and Northern countries; shellfish in Spain; and root vegetables in Northern and Central Europe. Large inter-centre variation, however, existed in some countries.
Dark bread, root vegetables and fish are strongly related to a Nordic dietary tradition. Apples/pears, berries, cabbages, fish, shellfish and root vegetables are broadly consumed in Europe, and may thus be included in regional public health campaigns.
Full-text · Article · Mar 2014 · Public Health Nutrition
[Show abstract][Hide abstract] ABSTRACT: There is limited evidence for an association between the pattern of lifetime alcohol use and cause-specific risk of death.
Multivariable hazard ratios were estimated for different causes of death according to patterns of lifetime alcohol consumption using a competing risks approach: 111 953 men and 268 442 women from eight countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study were included. Self-reported alcohol consumption at ages 20, 30, 40 or 50 years and at enrolment were used for the analysis; 26 411 deaths were observed during an average of 12.6 years of follow-up.
The association between lifetime alcohol use and death from cardiovascular diseases was different from the association seen for alcohol-related cancers, digestive, respiratory, external and other causes. Heavy users (>5 drinks/day for men and >2.5 drinks/day for women), regardless of time of cessation, had a 2- to 5-times higher risk of dying due to alcohol-related cancers, compared with subjects with lifetime light use (≤1 and ≤0.5 drink/week for men and women, respectively). Compared with lifetime light users, men who used <5 drinks/day throughout their lifetime had a 24% lower cardiovascular disease mortality (95% confidence interval 2-41). The risk of death from coronary heart disease was also found to be 34-46% lower among women who were moderate to occasionally heavy alcohol users compared with light users. However, this relationship was only evident among men and women who had no chronic disease at enrolment.
Limiting alcohol use throughout life is associated with a lower risk of death, largely due to cardiovascular disease but also other causes. However, the potential health benefits of alcohol use are difficult to establish due to the possibility of selection bias and competing risks related to diseases occurring later in life.
Full-text · Article · Dec 2013 · International Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: The etiology of leukemias cannot entirely be explained by known risk factors, including ionizing radiation, benzene exposure, and infection with human T cell leukemia virus. A number of studies suggested that diet influences the risk of adult leukemias. However, results have been largely inconsistent. We examined the potential association between dietary factors and risk of leukemias among participants of the European Prospective Investigation into Cancer and Nutrition study. Among the 477,325 participants with mean follow-up of 11.34 yr (SD = 2.47), 773 leukemias (373 and 342 cases of lymphoid and myeloid leukemia, respectively) were identified. Diet over the previous 12 mo was assessed at baseline using a validated country-specific dietary questionnaire. Cox proportional hazards regression was used to explore the association between dietary factors that have previously been associated with leukemia risk, including red and processed meat, poultry, offal, fish, dairy products, vegetables, fruits, and seeds/nuts, and risk of both lymphoid and myeloid leukemias. No significant associations were observed between dietary measures and total, lymphoid, and myeloid leukemias. Additional subtype analyses showed no dietary association with risk of major subtypes of leukemias. In summary, this study did not support a possible link between selected dietary factors and risk of leukemias.
Full-text · Article · Nov 2013 · Nutrition and Cancer
[Show abstract][Hide abstract] ABSTRACT: This study describes the distribution of glycosylated haemoglobin (HbA1c) and glucose concentrations in the combined year 1 (2008-2009), year 2 (2009-2010) and year 3 (2010-2011) of the National Diet and Nutrition Survey (NDNS) rolling programme. The NDNS rolling programme is a nationally representative survey of food consumption, nutrient intakes and nutritional status of people aged 1.5 years and over living in England, Wales, Scotland and Northern Ireland. The study population comprised survey members who completed three or four days of dietary recording and who provided a blood sample. After excluding survey members with self-reported diabetes (n=25), there were 1016 results for HbA1c and 942 for glucose (not the same individuals in each case). Around 5.4% of men and 1.7% of women aged 19-64 years, and 5.1% of men and 5.9% of women aged ≥65 years had impaired fasting glucose (glucose concentrations 6.1-6.9 mmol/L). Over 20% of men aged ≥65 years had fasting glucose concentrations above the clinical cut-off for diabetes (≥7 mmol/L) compared to 2.1% of women of similar age (p=0.007). Similarly, 16.4% of men had HbA1c concentrations ≥6.5%, compared to 1.5% of women (p=0.003). Children and teenagers had fasting glucose and HbA1c values largely within the normal range. To conclude, this is the first study to provide data on the distribution of HbA1c and glucose concentrations in a nationally representative sample of the British population. The high prevalence of men aged ≥65 years with HbA1c and glucose concentrations above the clinical cut-off of diabetes warrants further attention.
Full-text · Article · Sep 2013 · Journal of epidemiology and community health
[Show abstract][Hide abstract] ABSTRACT: Considerable variation in 25-hydroxyvitamin D (25(OH)D) in populations worldwide that seems to be independent of latitude has been reported. Therefore, we aimed to assess vitamin D status of a mid-aged German general population and to identify its dietary, lifestyle, anthropometric, and genetic determinants.
25(OH)D concentrations were measured by LC-MS/MS in plasma samples of a random subcohort of the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) comprising 2,100 subjects aged 35-65 years. Associations between potential predictors and 25(OH)D were assessed by linear regression models.
32.8 % of the variance in 25(OH)D was explained by a multivariable regression model, with season being the by far strongest predictor (semi-partial R (2): 14.6 %). Sex, waist circumference, leisure time physical activity, smoking, polymorphisms in the GC, CYP2R1, and DHCR7 genes, supplement use, exogenous hormone use, alcohol consumption, egg consumption, and fish consumption were significantly associated with 25(OH)D concentrations as well. However, none of these factors explained >2.3 % of the variance in 25(OH)D.
Even with a comprehensive set of genetic, anthropometric, dietary, and lifestyle correlates, not more than 32.8 % of the variation in 25(OH)D could be explained in the EPIC-Germany study, implying that vitamin D prediction scores may not provide an appropriate proxy for measured 25(OH)D. Food intake was only a weak predictor of 25(OH)D concentrations, while a strong seasonal fluctuation in 25(OH)D was shown.
No preview · Article · Sep 2013 · European Journal of Nutrition
[Show abstract][Hide abstract] ABSTRACT: It is unclear whether vitamin D lowers risk of type 2 diabetes (T2D). In an observational study, we assessed the prospective association between plasma 25-hydroxyvitamin D (25(OH)D) and incident T2D, and evaluated whether it holds up for genetically determined elevated 25(OH)D. We used a case-cohort study nested within the German arm of the European Prospective Investigation into Cancer. From a total cohort of 53,088 participants with a mean follow-up of 6.6 years, we identified a random subcohort of 2,121 participants (57 % women) and 1,572 incident cases of T2D. 25(OH)D was measured in baseline plasma samples retrieved from frozen storage. Mean plasma 25(OH)D in the subcohort was 47.1 (5th-95th percentile 19.6-80.7) nmol/L. After controlling for age, sex, center, season of blood draw, education, and lifestyle, the hazard of T2D decreased across increasing plasma concentrations of 25(OH)D (P linear trend <0.0001). The association became non-linear after adjustment for BMI and waist circumference (P non-linearity <0.0001), with the inverse association being restricted to participants with 25(OH)D concentrations below ~45 nmol/L (hazard ratio per 5 nmol/L higher 25(OH)D 0.91, 95 % CI 0.84-0.98). A score predicting genetically determined plasma 25(OH)D by weighting four independent single-nucleotide polymorphisms by their effect on 25(OH)D, explained 3.7 % of the variance in 25(OH)D. The hazard ratio (95 % CI) per 5 nmol/L higher genetically predicted 25(OH)D was 0.98 (0.89-1.08) in the entire study sample and 1.06 (0.93-1.21) in the sub-sample with 25(OH)D <45 nmol/L. This latter finding casts doubt on a strong causal association of 25(OH)D with T2D, but further research in large-scale consortia is needed.
No preview · Article · Sep 2013 · European Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Prospective studies have consistently reported lower colorectal cancer risks associated with higher intakes of total dairy products, total milk and dietary calcium. However, less is known about whether the inverse associations vary for individual dairy products with differing fat contents.
In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between intakes of total milk and milk subtypes (whole-fat, semi-skimmed and skimmed), yoghurt, cheese, and dietary calcium with colorectal cancer risk amongst 477,122 men and women. Dietary questionnaires were administered at baseline. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for relevant confounding variables.
During the mean 11 years of follow-up, 4,513 incident cases of colorectal cancer occurred. After multivariable adjustments, total milk consumption was inversely associated with colorectal cancer risk (HR per 200 g/day 0.93, 95% CI: 0.89-0.98). Similar inverse associations were observed for whole-fat (HR per 200 g/day 0.90, 95% CI: 0.82-0.99) and skimmed milk (HR per 200 g/day 0.90, 95% CI: 0.79-1.02) in the multivariable models. Inverse associations were observed for cheese and yoghurt in the categorical models; although in the linear models, these associations were non-significant. Dietary calcium was inversely associated with colorectal cancer risk (HR per 200 mg/day 0.95, 95% CI: 0.91-0.99); this association was limited to dairy sources of calcium only (HR per 200 mg/day 0.95, 95% CI: 0.91-0.99), with no association observed for non-dairy calcium sources (HR per 200 mg/day 1.00, 95% CI: 0.81-1.24).
Our results strengthen the evidence for a possible protective role of dairy products on colorectal cancer risk. The inverse associations we observed did not differ by the fat content of the dairy products considered.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to examine the prospective association between life satisfaction and risk of type 2 diabetes mellitus, myocardial infarction, stroke, and cancer. Previous studies suggested that psychosocial factors may affect the development of chronic diseases but the impact of positive attitudes, in particular life satisfaction, is yet to be determined.
The analysis included 50,358 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study in Potsdam and Heidelberg. Life satisfaction was assessed in a baseline interview and incident cases of chronic diseases were identified and verified during follow-up. Hazard ratios were calculated using Cox proportional hazards regression models that were systematically multivariable-adjusted for established risk factors and prevalent diseases.
During an average of 8 years of follow-up 2,293 cases of cancer, 1,840 cases of type 2 diabetes mellitus, 440 cases of stroke, and 562 cases of myocardial infarction were observed. Women who were unsatisfied with life at baseline showed in all models a significantly increased risk of cancer (HR: 1.45; 95% CI: 1.18-1.78) and stroke (HR: 1.69; 95% CI: 1.05-2.73) as well as an increased risk of type 2 diabetes mellitus by trend across categories (p-trend=0.04) compared to women very satisfied with life. In men, a relationship between life satisfaction and stroke was found but did not persist after consideration of lifestyle factors and prevalent diseases. No significant association was observed between life satisfaction and risk of myocardial infarction.
The results of this study suggest that reduced life satisfaction is related to the development of chronic diseases-particularly in women and partly mediated by established risk factors.
[Show abstract][Hide abstract] ABSTRACT: Circulating 25-hydroxyvitamin D (25(OH)D) has been associated with cardiovascular disease (CVD) risk in observational studies. Also, SNPs to explain variation in 25(OH)D have been identified by genome-wide association studies. Detection of direct associations between SNPs that significantly affect 25(OH)D and CVD risk would indicate a causal role of vitamin D, as reverse causation could be excluded and confounding could be better controlled. Thus, a combined analysis of candidate SNPs in relation to circulating 25(OH)D and CVD risk was carried out. A case-cohort study within the EPIC-Germany study was conducted comprising a randomly drawn subcohort of 2,132 subjects (57.9% women, mean age: 50.6 years) and incident cases of myocardial infarction (n=559) and stroke (n=471) that occurred during a mean follow-up duration of 7.6 years. 25(OH)D concentrations were measured by LC-MS/MS in baseline plasma samples. Additionally, eight candidate SNPs were assayed. Associations between 25(OH)D, SNPs and the risks of myocardial infarction and stroke were assessed by multivariable regression analyses. Mean 25(OH)D level was 47.2 nmol/L in the subcohort. Four SNPs were associated with 25(OH)D (p<0.05). In subjects with 25(OH)D levels <25 nmol/L, the risks of CVD as composite endpoint (Hazard Ratio: 1.53, 95% confidence interval: 1.12-2.09), myocardial infarction, and stroke were significantly increased compared to subjects with levels ≥50 nmol/L, while no significant linear associations were observed. A SNP score was not related to the risks of total CVD (Hazard Ratio: 1.0, 95% confidence interval: 0.71-1.42), myocardial infarction, or stroke. The same was true concerning single SNPs. Given the lack of association between SNPs and the risks of stroke and myocardial infarction, the present findings do not point to a major causal role of vitamin D in the development of these diseases. However, a detection of modest associations between genetic markers and CVD risk in larger consortia cannot be ruled out.