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Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study
Joshua P Sutherland1, Ang Zhou2, Elina Hyppönen2
1Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia (J.P.S.).
Background:
Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking.
Objective:
To assess genetic evidence for the causal role of low vitamin D status in mortality.
Design:
Nonlinear Mendelian randomization analyses.
Setting:
UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010.
Participants:
307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data.
Measurements:
Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020.
Results:
There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L.
Limitations:
Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate.
Conclusion:
Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels.
Primary Funding Source:
National Health and Medical Research Council.
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