LONDON, UK — Elevated levels of vitamin D may well lower blood pressure and reduce the risk of hypertension, an analysis of gene variants in several large cohorts cautiously suggests^[1].

The study found that the presence of several specific genetic mutations associated with reduced metabolic synthesis of plasma 25-hydroxyvitamin D (25[OH]D) correlated inversely and significantly with both systolic and diastolic blood pressure and with the risk of having hypertension by standard criteria.

"This finding lends support to continued efforts to prevent vitamin-D deficiency," according to the study's authors, led by Dr Karani S Vimaleswaran (UCL Institute of Child Health, London, UK), reporting June 26, 2014 in Lancet Diabetes & Endocrinology. If the findings are replicated convincingly, they write, they "strengthen the case for appropriately powered, well-designed randomized clinical trials to investigate the necessary vitamin-D doses and appropriate target groups for the prevention or treatment of hypertension."

Crucially, the study could conclude that elevated vitamin-D levels may be causally associated with reduced blood pressure because it relied on Mendelian randomization in observational cohorts to mimic the statistical properties of a prospective randomized trial. In effect, the gene variants measured in the analysis served as a stand-in for levels of 25(OH)D that would have been obtained in such a clinical trial.

An accompanying commentary from Drs Shoaib Afzal and Børge G Nordestgaard (University of Copenhagen, Denmark) notes at least two important differences in how a Mendelian randomization study of vitamin D and blood pressure might be interpreted compared with a standard randomized trial^[2]. A study of gene variants that influence plasma 25(OH)D levels "might capture the variation caused by one or more of the three potential sources of vitamin D (sun exposure, diet, and supplements) rather than the effect of supplements only, as assessed in randomized trials." Also, the gene study would reflect lifelong exposure to 25(OH)D, rather than for a discrete follow-up time.

"Thus, estimates from randomized intervention trials might be somewhat attenuated compared with estimates from Mendelian randomization studies."

The current study is timely and "an important step toward delineation of the role of low vitamin-D concentrations in the pathogenesis of hypertension," they write. Not only will the results need to be confirmed, also useful would be signs of "a corresponding benefit for the prevention of diseases caused by hypertension such as stroke."

The cohorts included >100 000 persons from 35 studies that were part of the D-CarDia Collaboration looking at vitamin D and cardiovascular risk in people of European ancestry in both Europe and North America.

In a phenotype analysis based on almost 50 000 people in the Di-CarDia studies, every 10% increment in 25(OH)D concentration corresponded to a 0.12-mm-Hg drop (p=0.003) in systolic blood pressure and 2% reduced odds of hypertension (p=0.0003), but no significant relation to diastolic BP. Those associations didn't vary by age, sex, method of BP measurement, or body-mass index.

In the Mendelian association analysis of Di-CarDia studies, every increment in a vitamin-D synthesis score based on 25(OH)D-related alleles—increments that corresponded to a 10% rise in 25(OH)D concentrations—was associated with a 0.37-mm-Hg fall in systolic BP (p=0.052), a 0.29-mm-Hg drop in diastolic BP (p=0.01), and an odds ratio (OR) of 0.92 (95% CI 0.87–0.97) for hypertension (p=0.002).

In other analyses, Di-CarDia data were statistically enriched by combining them with other large sets of blood-pressure genetics data.

In one that included >146 000 persons, synthesis score increment corresponded to a 0.10-mm-Hg drop in systolic BP (p=0.0001) and 0.08-mm-Hg fall in diastolic BP (p=0.01).

In a different combination of D-CarDia and other data, one that included >142 000 persons, the vitamin-D synthesis score was associated with an odds ratio (OR) of 0.98 (95% CI 0.96–0.99) for hypertension (p=0.001).

"Our findings are biologically plausible," the group writes, in that activation of the renin-angiotensin system raises BP and CV risk and some clinical and experimental evidence suggests inconclusively that increased vitamin-D levels suppress plasma renin activity.

Vimaleswaran reported no conflicts of interest; disclosures for the coauthors are listed in the paper. Afzal and Nordestgaard stated they had no competing interests.