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
(2021) The Lancet Diabetes and Endocrinology, volume 9, issue 12, pp. 837 - 846
(Article)
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
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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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Keywords: Journal Article
ISSN: 2213-8587
Publisher: Elsevier
Note: Funding Information: We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council (MRC) Epidemiology Unit for sample management, Cambridge Genomic Services for genotyping, Matthew Walker and Sarah Spackman (British Heart Foundation [BHF] Cardiovascular Epidemiology Unit, Cambridge, UK) for data management, Nicola Kerrison (MRC Epidemiology Unit, Cambridge, UK) for managing the data for the InterAct Project, the laboratory team at VITAS Analytical Services, especially Anne Marte Haug, for vitamin D assays in EPIC-CVD, and the team at the EPIC-CVD Coordinating Centre for study coordination and administration. We acknowledge the use of data and biological samples from the EPIC-Ragusa cohort and the EPIC-Asturias cohort. A full list of Emerging Risk Factors Collaboration / Vitamin D Studies Collaboration investigators is provided in the appendix. This research has been done using the UK Biobank Resource under Application Number 11833. No specific funding was obtained for this manuscript. EPIC-CVD was funded by the European Research Council (268834) and the European Commission Framework Programme 7 (HEALTH-F2–2012–279233). The coordinating centre was supported by core funding from the UK Medical Research Council (G0800270; MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), and the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215–20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. AMM is funded by the EC-Innovative Medicines Initiative (BigData@Heart). LS is funded by a BHF Programme Grant (RG/18/13/33946). TRB is funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014–10024) and a BHF Programme Grant (RG/18/13/33946). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (award number 204623/Z/16/Z), and by the UK Research and Innovation Medical Research Council (MC_UU_00002/7). RC is funded by a BHF PhD studentship (FS/18/56/34177). EA was funded by the EC-Innovative Medicines Initiative (BigData@Heart) and a BHF Programme Grant (RG/18/13/33946). JD holds a BHF Professorship and a NIHR Senior Investigator Award. TJ is funded by the NIHR Cambridge Biomedical Research Centre (BRC-1215–20014). AMW is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). LAMP is funded by a BHF Programme Grant (RG/18/13/33946). TYNT is supported by a Nuffield Department of Population Health Intermediate Fellowship. MA is funded by a BHF Programme Grant (RG/18/13/33946). NJW, CL, and NGF acknowledge funding from the MRC Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5. FS is funded by the Chinese Scholarship Council, and Cambridge Commonwealth European and International Trust. NJW and NGF received support from the NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215–20014). DG is supported by the BHF Centre of Research Excellence (RE/18/4/34215) at Imperial College London and a National Institute for Health Research Clinical Lectureship (CL-2020–16–001) at St George's, University of London. CM is supported by the Federation Française de Cardiologie,. RZ-R was supported by the Miguel Servet type II programme (CPII20/00009) from the Institute of Health Carlos III (co-funded by the European Social Fund (ESF)—ESF investing in your future). YBS is partially funded by the NIHR School of Population Health Research. The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197). Measurements for 25(OH)D were funded jointly by the InterAct project, the EPIC-CVD project and the MRC Cambridge Initiative (RG71466, SJAH/004). EPIC-Oxford is supported by Cancer Research UK (C8221/A29017) and UK MRC (MR/M012190/1). The Longitudinal Aging Study Amsterdam (LASA) is supported by a grant from the Netherlands Ministry of Health, Welfare and Sport, Directorate of Long-Term Care. The Multi-Ethnic Study of Atherosclerosis is supported by grant R01HL096875 and contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159,75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health (NIH) funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NCATS, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. MrOS data is available online . The Study of Osteoporotic Fractures is supported by NIH funding. NIA provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The Study of Health in Pomerania-1 is part of the Community Medicine Research network of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, and Institut National de la Santé e de la Recherche Médicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, Statistics Netherlands (the Netherlands); Austrian Research Promotion Agency (Austria); Health Research Fund - Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (UK). Funding Information: We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council (MRC) Epidemiology Unit for sample management, Cambridge Genomic Services for genotyping, Matthew Walker and Sarah Spackman (British Heart Foundation [BHF] Cardiovascular Epidemiology Unit, Cambridge, UK) for data management, Nicola Kerrison (MRC Epidemiology Unit, Cambridge, UK) for managing the data for the InterAct Project, the laboratory team at VITAS Analytical Services, especially Anne Marte Haug, for vitamin D assays in EPIC-CVD, and the team at the EPIC-CVD Coordinating Centre for study coordination and administration. We acknowledge the use of data and biological samples from the EPIC-Ragusa cohort and the EPIC-Asturias cohort. A full list of Emerging Risk Factors Collaboration / Vitamin D Studies Collaboration investigators is provided in the appendix. This research has been done using the UK Biobank Resource under Application Number 11833. No specific funding was obtained for this manuscript. EPIC-CVD was funded by the European Research Council (268834) and the European Commission Framework Programme 7 (HEALTH-F2–2012–279233). The coordinating centre was supported by core funding from the UK Medical Research Council (G0800270; MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), and the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215–20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. AMM is funded by the EC-Innovative Medicines Initiative (BigData@Heart). LS is funded by a BHF Programme Grant (RG/18/13/33946). TRB is funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014–10024) and a BHF Programme Grant (RG/18/13/33946). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (award number 204623/Z/16/Z), and by the UK Research and Innovation Medical Research Council (MC_UU_00002/7). RC is funded by a BHF PhD studentship (FS/18/56/34177). EA was funded by the EC-Innovative Medicines Initiative (BigData@Heart) and a BHF Programme Grant (RG/18/13/33946). JD holds a BHF Professorship and a NIHR Senior Investigator Award. TJ is funded by the NIHR Cambridge Biomedical Research Centre (BRC-1215–20014). AMW is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). LAMP is funded by a BHF Programme Grant (RG/18/13/33946). TYNT is supported by a Nuffield Department of Population Health Intermediate Fellowship. MA is funded by a BHF Programme Grant (RG/18/13/33946). NJW, CL, and NGF acknowledge funding from the MRC Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5. FS is funded by the Chinese Scholarship Council, and Cambridge Commonwealth European and International Trust. NJW and NGF received support from the NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215–20014). DG is supported by the BHF Centre of Research Excellence (RE/18/4/34215) at Imperial College London and a National Institute for Health Research Clinical Lectureship (CL-2020–16–001) at St George's, University of London. CM is supported by the Federation Française de Cardiologie,. RZ-R was supported by the Miguel Servet type II programme (CPII20/00009) from the Institute of Health Carlos III (co-funded by the European Social Fund (ESF)—ESF investing in your future). YBS is partially funded by the NIHR School of Population Health Research. The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197). Measurements for 25(OH)D were funded jointly by the InterAct project, the EPIC-CVD project and the MRC Cambridge Initiative (RG71466, SJAH/004). EPIC-Oxford is supported by Cancer Research UK (C8221/A29017) and UK MRC (MR/M012190/1). The Longitudinal Aging Study Amsterdam (LASA) is supported by a grant from the Netherlands Ministry of Health, Welfare and Sport, Directorate of Long-Term Care. The Multi-Ethnic Study of Atherosclerosis is supported by grant R01HL096875 and contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159,75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health (NIH) funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NCATS, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. MrOS data is available online. The Study of Osteoporotic Fractures is supported by NIH funding. NIA provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The Study of Health in Pomerania-1 is part of the Community Medicine Research network of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, and Institut National de la Santé e de la Recherche Médicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, Statistics Netherlands (the Netherlands); Austrian Research Promotion Agency (Austria); Health Research Fund - Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (UK). Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
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