TY - JOUR

T1 - Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality

T2 - observational and Mendelian randomisation analyses

AU - Sofianopoulou, Eleni

AU - Kaptoge, Stephen K.

AU - Afzal, Shoaib

AU - Jiang, Tao

AU - Gill, Dipender

AU - Gundersen, Thomas E.

AU - Bolton, Thomas R.

AU - Allara, Elias

AU - Arnold, Matthew G.

AU - Mason, Amy M.

AU - Chung, Ryan

AU - Pennells, Lisa A.M.

AU - Shi, Fanchao

AU - Sun, Luanluan

AU - Willeit, Peter

AU - Forouhi, Nita G.

AU - Langenberg, Claudia

AU - Sharp, Stephen J.

AU - Panico, Salvatore

AU - Engström, Gunnar

AU - Melander, Olle

AU - Tong, Tammy Y.N.

AU - Perez-Cornago, Aurora

AU - Norberg, Margareta

AU - Johansson, Ingegerd

AU - Katzke, Verena

AU - Srour, Bernard

AU - José Sánchez, María

AU - Redondo-Sánchez, Daniel

AU - Olsen, Anja

AU - Dahm, Christina C.

AU - Overvad, Kim

AU - Brustad, Magritt

AU - Skeie, Guri

AU - Moreno-Iribas, Conchi

AU - Onland-Moret, N. Charlotte

AU - van der Schouw, Yvonne T.

AU - Tsilidis, Konstantinos K.

AU - Heath, Alicia K.

AU - Agnoli, Claudia

AU - Krogh, Vittorio

AU - de Boer, Ian H.

AU - Kobylecki, Camilla Jannie

AU - Çolak, Yunus

AU - Zittermann, Armin

AU - Sundström, Johan

AU - Welsh, Paul

AU - Schierbeck, Louise L.

AU - Linneberg, Allan

AU - Nordestgaard, Børge G.

AU - Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration

N1 - Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1016/S2213-8587(21)00263-1

DO - 10.1016/S2213-8587(21)00263-1

M3 - Journal article

C2 - 34717822

AN - SCOPUS:85119591845

VL - 9

SP - 837

EP - 846

JO - The Lancet Diabetes & Endocrinology

JF - The Lancet Diabetes & Endocrinology

SN - 2213-8587

IS - 12

ER -