Effect of genetically low 25-hydroxyvitamin d on mortality risk: Mendelian randomization analysis in 3 large European cohorts

Journal article


Aspelund, Thor, Grubler, Martin R., Smith, Albert V., Gudmundsson, Elias F., Keppel, Martin, Cotch, Mary Frances, Harris, Tamara B., Jorde, Rolf, Grimnes, Guri, Joakimsen, Ragnar Martin, Schirmer, Henrik, Wilsgaard, Tom, Mathiesen, Ellisiv Bøgeberg, Njolstad, Inger, Loechen, Maja-Lisa, Marz, Winfried, Kleber, Marcus E., Tomaschitz, Andreas, Grove-Laugesen, Diana, ... Cashman, Kevin D. 2019. Effect of genetically low 25-hydroxyvitamin d on mortality risk: Mendelian randomization analysis in 3 large European cohorts. Nutrients. 11 (1), pp. 1 - 12. https://doi.org/10.3390/nu11010074
AuthorsAspelund, Thor, Grubler, Martin R., Smith, Albert V., Gudmundsson, Elias F., Keppel, Martin, Cotch, Mary Frances, Harris, Tamara B., Jorde, Rolf, Grimnes, Guri, Joakimsen, Ragnar Martin, Schirmer, Henrik, Wilsgaard, Tom, Mathiesen, Ellisiv Bøgeberg, Njolstad, Inger, Loechen, Maja-Lisa, Marz, Winfried, Kleber, Marcus E., Tomaschitz, Andreas, Grove-Laugesen, Diana, Rejnmark, Lars, Swart, Karin M. A., Brouwer, Ingeborg A., Lips, Paul, van Schoor, Natasja M., Sempos, Christopher T., Durazo-Arvizu, Ramon A., Skrabakova, Zuzana, Dowling, Kristen G. and Cashman, Kevin D.
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.

KeywordsVitamin D; standardized 25(OH)D; Mendelian randomization; mortality; cohorts; Individual Participant Data
Year2019
JournalNutrients
Journal citation11 (1), pp. 1 - 12
PublisherMDPI AG
ISSN2072-6643
Digital Object Identifier (DOI)https://doi.org/10.3390/nu11010074
Scopus EID2-s2.0-85059500485
Open accessOpen access
Page range1 - 12
Research GroupMary MacKillop Institute for Health Research
Publisher's version
License
Place of publicationSwitzerland
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https://acuresearchbank.acu.edu.au/item/86052/effect-of-genetically-low-25-hydroxyvitamin-d-on-mortality-risk-mendelian-randomization-analysis-in-3-large-european-cohorts

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