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Observational Study
. 2021 Dec;9(12):837-846.
doi: 10.1016/S2213-8587(21)00263-1. Epub 2021 Oct 28.

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

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Observational Study

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

Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration. Lancet Diabetes Endocrinol. 2021 Dec.

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Abstract

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, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration 0·69 [95% CI 0·59-0·80]; p<0·0001) and non-significant inverse associations for stroke (0·85 [0·70-1·02], p=0·09) and coronary heart disease (0·89 [0·76-1·04]; p=0·14). A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D concentrations and all-cause mortality up to around 40 nmol/L.

Interpretation: Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies.

Funding: British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

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Conflict of interest statement

Declaration of interests ASB reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer, and Sanofi and personal fees from Novartis. JD reports grants, personal fees, and non-financial support from Merck Sharp & Dohme, grants, personal fees, and non-financial support from Novartis, grants from Pfizer, and grants from AstraZeneca outside the submitted work. YÇ reports personal fees from Boehringer Ingelheim, AstraZeneca, and Sanofi Genzyme outside the submitted work. BGN reports consultancies and talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics outside submitted work. MA is now an employee of AstraZeneca. DG is employed part-time by Novo Nordisk. PW reports grant income from Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, and Novartis outside the submitted work. NS reports personal fees from Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp and Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, and grant funding paid to his institution from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Observational associations of 25(OH)D concentration with outcomes Reference value is 50 nmol/L. The shaded area represents the 95% CI for the dose—response curve. 25(OH)D=25-hydroxyvitamin D. CHD=coronary heart disease. CVD=cardiovascular disease.
Figure 2
Figure 2
Mendelian randomisation estimates for primary outcomes in overall population and strata of residual 25(OH)D concentrations Estimates (95% CIs) represent odds ratios per 10 nmol/L increase in genetically-predicted concentration of 25(OH)D in strata of the population defined by residual concentration of 25(OH)D.
Figure 3
Figure 3
Mendelian randomisation estimates for cause-specific mortality in overall population and strata of residual 25(OH)D concentrations Estimates (95% CIs) represent odds ratios per 10 nmol/L increase in genetically-predicted concentration of 25(OH)D in strata of the population defined by residual concentration of 25(OH)D. 25(OH)D=25-hydroxyvitamin D.
Figure 4
Figure 4
Mendelian randomisation estimates for finer stratification of residual 25(OH)D concentrations at 5 nmol/L intervals Estimates (95% CIs) represent odds ratios per 10 nmol/L increase in genetically-predicted vitamin D concentration in strata of the population defined by residual concentration of 25(OH)D. Points are plotted on the horizontal axis at the central value of each stratum (22·5 nmol/L for the <25 nmol/L stratum, 27·5 nmol/L for the 25–30 nmol/L stratum, and so on). 25(OH)D=25-hydroxyvitamin D. OR=odds ratio.

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