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Nutrients. 2019 Jan 2;11(1). pii: E74. doi: 10.3390/nu11010074.

Effect of Genetically Low 25-Hydroxyvitamin D on Mortality Risk: Mendelian Randomization Analysis in 3 Large European Cohorts.

Author information

1
Icelandic Heart Association, 201 Kopavogur, Iceland. thor@hi.is.
2
Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. thor@hi.is.
3
Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria. martin.gruebler@gmx.net.
4
Department of Cardiology, Medical University of Graz, 8036 Graz, Austria. martin.gruebler@gmx.net.
5
Swiss Cardiovascular Center Bern, Department of Cardiology, Bern University Hospital, University of Bern, 3012 Bern, Switzerland. martin.gruebler@gmx.net.
6
Icelandic Heart Association, 201 Kopavogur, Iceland. albertvs@umich.edu.
7
Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. albertvs@umich.edu.
8
Icelandic Heart Association, 201 Kopavogur, Iceland. elias@hjarta.is.
9
Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria. keppel.martin@gmail.com.
10
Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, MD 20892-1204, USA. mfc@nei.nih.gov.
11
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD 20814, USA. tamara.b.harris@gmail.com.
12
Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. rolf.jorde@unn.no.
13
Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. guri.grimnes@uit.no.
14
Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. ragnar.joakimsen@uit.no.
15
Tromsø Cardiovascular Research Group UNN, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. henrik.schirmer@uit.no.
16
Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. tom.wilsgaard@uit.no.
17
Brain and Circulation Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. ellisiv.mathiesen@uit.no.
18
Department of Neurology, University Hospital of North Norway, 9038 Tromsø, Norway. ellisiv.mathiesen@uit.no.
19
Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. inger.njolstad@uit.no.
20
Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. maja-lisa.lochen@uit.no.
21
Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany. Winfried.Maerz@synlab.com.
22
SYNLAB Academy, SYNLAB Holding Deutschland GmbH, P5, 7, D-68161 Mannheim or Gubener Straße 39, 86156 Augsburg, Germany. Winfried.Maerz@synlab.com.
23
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria. Winfried.Maerz@synlab.com.
24
Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany. Marcus.Kleber@medma.uni-heidelberg.de.
25
NutriCard-Competence Cluster for Nutrition and Cardiovascular Health, Institute for Nutritional Science, Friedrich-Schiller-University, 07743 Jena, Germany. Marcus.Kleber@medma.uni-heidelberg.de.
26
Department of Cardiology, Medical University of Graz, 8036 Graz, Austria. andreas.tomaschitz@medunigraz.at.
27
Specialist Clinic for Rehabilitation Bad Aussee, 8990 Bad Aussee, Austria. andreas.tomaschitz@medunigraz.at.
28
Department of Internal Medicine-Cardiology, Charité University Hospital Berlin, Campus Virchow Klinikum, 10117 Berlin, Germany. andreas.tomaschitz@medunigraz.at.
29
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark. jenngrov@rm.dk.
30
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark. lars.rejnmark@rm.dk.
31
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands. k.swart@vumc.nl.
32
Department of Health Sciences, Faculty of Sciences and Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands. ingeborg.brouwer@vu.nl.
33
Department of Internal Medicine, Endocrine Section, VU University Medical Center, 1081 Amsterdam, The Netherlands. P.Lips@vumc.nl.
34
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands. nm.vanschoor@vumc.nl.
35
Office of Dietary Supplements, National Institute of Health, Bethesda, MD 20892-7517, USA. semposch@gmail.com.
36
Department of Public Health Sciences, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA. rdurazo@LUC.edu.
37
Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland. zuzkani@gmail.com.
38
Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland. 115224470@umail.ucc.ie.
39
Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland. K.Cashman@ucc.ie.
40
Department of Medicine, University College Cork, Cork T12K8AF, Ireland. K.Cashman@ucc.ie.
41
Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland. M.Kiely@ucc.ie.
42
Irish Centre for Fetal and Neonatal Translational Research [INFANT], University College Cork, Cork T12K8AF, Ireland. M.Kiely@ucc.ie.
43
Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria. stefan.pilz@chello.at.
44
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands. stefan.pilz@chello.at.
45
Icelandic Heart Association, 201 Kopavogur, Iceland. v.gudnason@hjarta.is.
46
Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. v.gudnason@hjarta.is.
47
Icelandic Heart Association, 201 Kopavogur, Iceland. gudny@hjarta.is.

Abstract

The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15⁻1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80⁻2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

KEYWORDS:

Individual Participant Data; Mendelian randomization; Vitamin D; cohorts; mortality; standardized 25(OH)D

PMID:
30609725
DOI:
10.3390/nu11010074
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