Nutrients (Jan 2019)
Effect of Genetically Low 25-Hydroxyvitamin D on Mortality Risk: Mendelian Randomization Analysis in 3 Large European Cohorts
- Thor Aspelund,
- Martin R. Grübler,
- Albert V. Smith,
- Elias F. Gudmundsson,
- Martin Keppel,
- Mary Frances Cotch,
- Tamara B. Harris,
- Rolf Jorde,
- Guri Grimnes,
- Ragnar Joakimsen,
- Henrik Schirmer,
- Tom Wilsgaard,
- Ellisiv B. Mathiesen,
- Inger Njølstad,
- Maja-Lisa Løchen,
- Winfried März,
- Marcus E. Kleber,
- Andreas Tomaschitz,
- Diana Grove-Laugesen,
- Lars Rejnmark,
- Karin M. A. Swart,
- Ingeborg A. Brouwer,
- Paul Lips,
- Natasja M. van Schoor,
- Christopher T. Sempos,
- Ramón A. Durazo-Arvizu,
- Zuzana Škrabáková,
- Kirsten G. Dowling,
- Kevin D. Cashman,
- Mairead Kiely,
- Stefan Pilz,
- Vilmundur Gudnason,
- Gudny Eiriksdottir
Affiliations
- Thor Aspelund
- Icelandic Heart Association, 201 Kopavogur, Iceland
- Martin R. Grübler
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria
- Albert V. Smith
- Icelandic Heart Association, 201 Kopavogur, Iceland
- Elias F. Gudmundsson
- Icelandic Heart Association, 201 Kopavogur, Iceland
- Martin Keppel
- Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria
- Mary Frances Cotch
- Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, MD 20892-1204, USA
- Tamara B. Harris
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD 20814, USA
- Rolf Jorde
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Guri Grimnes
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Ragnar Joakimsen
- Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Henrik Schirmer
- Tromsø Cardiovascular Research Group UNN, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Tom Wilsgaard
- Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Ellisiv B. Mathiesen
- Brain and Circulation Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Inger Njølstad
- Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Maja-Lisa Løchen
- Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
- Winfried März
- Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany
- Marcus E. Kleber
- Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany
- Andreas Tomaschitz
- Department of Cardiology, Medical University of Graz, 8036 Graz, Austria
- Diana Grove-Laugesen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark
- Lars Rejnmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark
- Karin M. A. Swart
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands
- Ingeborg A. Brouwer
- Department of Health Sciences, Faculty of Sciences and Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands
- Paul Lips
- Department of Internal Medicine, Endocrine Section, VU University Medical Center, 1081 Amsterdam, The Netherlands
- Natasja M. van Schoor
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands
- Christopher T. Sempos
- Office of Dietary Supplements, National Institute of Health, Bethesda, MD 20892-7517, USA
- Ramón A. Durazo-Arvizu
- Department of Public Health Sciences, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA
- Zuzana Škrabáková
- Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland
- Kirsten G. Dowling
- Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland
- Kevin D. Cashman
- Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland
- Mairead Kiely
- Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland
- Stefan Pilz
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria
- Vilmundur Gudnason
- Icelandic Heart Association, 201 Kopavogur, Iceland
- Gudny Eiriksdottir
- Icelandic Heart Association, 201 Kopavogur, Iceland
- DOI
- https://doi.org/10.3390/nu11010074
- Journal volume & issue
-
Vol. 11,
no. 1
p. 74
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
- Vitamin D
- standardized 25(OH)D
- Mendelian randomization
- mortality
- cohorts
- Individual Participant Data