Vitamin D Deficiency Has Greater Risk for All-Cause Mortality

Observational epidemiological studies have consistently found that low concentrations of circulating 25-hydroxyvitamin D (25[OH]D), a metabolite used as a clinical indicator of vitamin D status, are associated with an increased risk of cardiovascular disease and all-cause mortality, as well as other chronic diseases.

An efficient approach for assessing the potential causal effect of vitamin D supplementation is Mendelian randomization. Mendelian randomization uses genetic variants specifically related to a particular exposure to compare genetically-defined population subgroups with different average levels of the exposure.


An international team of Medical Scientists in collaboration with and led by the University Hospital Würzburg (Wurzburg, Germany) undertook observational analyses using data from 33 prospective studies comprising 500,962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomization analyses were performed in four population-based cohort studies, comprising 386,406 middle-aged individuals of European ancestries, including 33,546 people who developed coronary heart disease, 18,166 people who had a stroke, and 27,885 people who died.

Primary outcomes were coronary heart disease, defined as fatal ischemic heart disease or non-fatal myocardial infarction; stroke, defined as any cerebrovascular disease; and all-cause mortality. The team measured concentrations of 25(OH)D in blood using the Liaison immunoassay analyser (DiaSorin; Saluggia, Italy) in the UK Biobank and Copenhagen studies, and liquid chromatography-tandem mass spectrometry in the EPIC-CVD study. In the Vitamin D Studies Collaboration (VitDSC), concentrations were measured by radioimmunoassay, direct chromatographic approaches, or other immunoassays. The team considered genetic variants from four gene regions previously shown to be strongly associated with 25(OH)D and implicated in the transport, metabolism, and synthesis of vitamin D: GC, DHCR7, CYP2R1, and CYP24A1. The GC gene encodes vitamin D binding protein.

The investigators reported that observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration (0.69) and non-significant inverse associations for stroke (0.85) and coronary heart disease (0.89). A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D concentrations and all-cause mortality up to around 40 nmol/L.

The authors concluded that they had found genetic evidence to suggest a causal relationship between 25(OH)D concentrations and mortality in individuals with low vitamin D status. The results have implications for the interpretation and design of vitamin D supplementation trials, and potential disease prevention strategies. The study was published on October 27, 2021in the journal The Lancet Diabetes & Endocrinology.

Related Links:
University Hospital Würzburg
DiaSorin