Association of Vitamin D Status With Arterial Blood Pressure and Hypertension Risk: A Mendelian Randomisation Study

Study Questions:

Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk. Using a Mendelian randomization approach, is 25(OH)D concentration causally associated with blood pressure and hypertension risk?


An allele score (25[OH]D synthesis score) was generated based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which was used as a proxy for 25(OH)D concentration. Meta-analyzed data were developed for up to 108,173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. The results of these analyses were complemented with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.


In phenotypic analyses (up to n = 49,363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, –0.12 mm Hg; 95% confidence interval [CI], –0.20 to –0.04; p = 0.003) and reduced odds of hypertension (odds ratio [OR], 0.98; 95% CI, 0.97–0.99; p = 0.0003), but not with decreased diastolic blood pressure. In meta-analyses in which the data from D-CarDia and combined with ICBP (n = 146,581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of –0.10 mm Hg in systolic blood pressure (–0.21 to –0.0001; p = 0.0498) and a change of –0.08 mm Hg in diastolic blood pressure (–0.15 to –0.02; p = 0.01). When D-CarDia and consortia data for hypertension were meta-analyzed together (n = 142,255), the synthesis score was associated with reduced odds of hypertension (OR per allele, 0.98; 0.96–0.99; p = 0.001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of –0.29 mm Hg in diastolic blood pressure (–0.52 to –0.07; p = 0.01), a change of –0.37 mm Hg in systolic blood pressure (–0.73 to 0.003; p = 0.052), and an 8.1% decreased odds of hypertension (OR, 0.92; 0.87–0.97; p = 0.002).


The authors concluded that increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.


The degree to which low levels of vitamin D are associated with each of the coronary disease risk factors and what, if any, supplemental dose will reduce cardiovascular risk requires appropriately powered clinical trials. The utility of using Mendelian randomization to measure the effects of variants of genes that affect biologic variables is gaining momentum, but one needs to realize that the results reflect the lifetime exposures.

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