Estimating dose—response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and revised Mendelian randomization analyses

Background Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Methods Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Findings Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95–1·01), stroke (1·01, [0·97–1·05]), or all-cause mortality (0·99, 0·95–1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations. Interpretation Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status

Estimating dose—response relationships for vitamin D with coronary heart disease, stroke, and allcause mortality: observational and revised Mendelian randomization analyses

Background: Randomized trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalizability of results to individuals with low vitamin D status is unclear. We characterized dose—response relationships between 25 hydroxyvitamin D [25(OH)D] concentrations and risk of coronary heart disease (CHD), stroke, and all-cause mortality in observational and Mendelian randomization frameworks. Methods: Observational analyses were conducted in 33 prospective studies comprising 500,962 individuals with no known history of CHD or stroke at baseline. Mendelian randomization analyses were conducted in four population-based cohort studies comprising 386,406 middle-aged individuals of European ancestries, including 33,546 CHD cases, 18,166 stroke cases, and 27,885 deaths. Findings: Observational analyses suggested threshold relationships for incident CHD, stroke, and mortality outcomes. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with CHD (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% confidence interval [CI] 0·95-1·01), stroke (OR 1·01, 95% CI 0·97-1·05), or all-cause mortality (OR 0·99, 95% CI 0·95-1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations. Interpretation: Stratified Mendelian randomization analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status