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

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  • Thor Aspelund, Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. thor@hi.is.
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  • Martin R Grübler, Swiss Cardiovascular Center Bern, Department of Cardiology, Bern University Hospital, University of Bern, 3012 Bern, Switzerland. martin.gruebler@gmx.net.
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  • Albert V Smith, Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. albertvs@umich.edu.
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  • Elias F Gudmundsson, Icelandic Heart Association, 201 Kopavogur, Iceland. elias@hjarta.is.
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  • Martin Keppel, Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria. keppel.martin@gmail.com.
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  • Mary Frances Cotch, Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, MD 20892-1204, USA. mfc@nei.nih.gov.
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  • Tamara B Harris, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD 20814, USA. tamara.b.harris@gmail.com.
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  • Rolf Jorde, Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. rolf.jorde@unn.no.
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  • Guri Grimnes, Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. guri.grimnes@uit.no.
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  • Ragnar Joakimsen, Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. ragnar.joakimsen@uit.no.
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  • Henrik Schirmer, Tromsø Cardiovascular Research Group UNN, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. henrik.schirmer@uit.no.
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  • Tom Wilsgaard, Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. tom.wilsgaard@uit.no.
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  • Ellisiv B Mathiesen, Department of Neurology, University Hospital of North Norway, 9038 Tromsø, Norway. ellisiv.mathiesen@uit.no.
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  • Inger Njølstad, Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. inger.njolstad@uit.no.
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  • Maja-Lisa Løchen, Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway. maja-lisa.lochen@uit.no.
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  • Winfried März, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria. Winfried.Maerz@synlab.com.
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  • Marcus E Kleber, NutriCard-Competence Cluster for Nutrition and Cardiovascular Health, Institute for Nutritional Science, Friedrich-Schiller-University, 07743 Jena, Germany. Marcus.Kleber@medma.uni-heidelberg.de.
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  • Andreas Tomaschitz, Department of Internal Medicine-Cardiology, Charité University Hospital Berlin, Campus Virchow Klinikum, 10117 Berlin, Germany. andreas.tomaschitz@medunigraz.at.
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  • Diana Grove-Laugesen, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark. jenngrov@rm.dk.
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  • Lars Rejnmark
  • Karin M A Swart, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands. k.swart@vumc.nl.
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  • Ingeborg A Brouwer, Department of Health Sciences, Faculty of Sciences and Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands. ingeborg.brouwer@vu.nl.
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  • Paul Lips, Department of Internal Medicine, Endocrine Section, VU University Medical Center, 1081 Amsterdam, The Netherlands. P.Lips@vumc.nl.
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  • Natasja M van Schoor, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands. nm.vanschoor@vumc.nl.
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  • Christopher T Sempos, Office of Dietary Supplements, National Institute of Health, Bethesda, MD 20892-7517, USA. semposch@gmail.com.
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  • Ramón A Durazo-Arvizu, Department of Public Health Sciences, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA. rdurazo@LUC.edu.
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  • Zuzana Škrabáková, Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland. zuzkani@gmail.com.
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  • Kirsten G Dowling, Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork T12K8AF, Ireland. 115224470@umail.ucc.ie.
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  • Kevin D Cashman, Department of Medicine, University College Cork, Cork T12K8AF, Ireland. K.Cashman@ucc.ie.
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  • Mairead Kiely, Irish Centre for Fetal and Neonatal Translational Research [INFANT], University College Cork, Cork T12K8AF, Ireland. M.Kiely@ucc.ie.
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  • Stefan Pilz, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands. stefan.pilz@chello.at.
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  • Vilmundur Gudnason, Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. v.gudnason@hjarta.is.
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  • Gudny Eiriksdottir, Icelandic Heart Association, 201 Kopavogur, Iceland. gudny@hjarta.is.

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.

OriginalsprogEngelsk
TidsskriftNutrients
Vol/bind11
Nummer1
ISSN2072-6643
DOI
StatusUdgivet - 2 jan. 2019
Eksternt udgivetJa

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