Meeting News CoveragePerspective

Evidence suggests causal link between vitamin D deficiency, hypertension

New genetic research has identified a causal link between increased plasma concentrations of 25-hydroxyvitamin D and reduced risk for hypertension.

Previous data suggested that low levels of vitamin D are associated with increased risk for CVD and death, and ongoing trials are assessing whether vitamin D supplementation may attenuate that risk. However, a causal link between vitamin D levels and hypertension had not been demonstrated, according to the study background.

“In view of the costs and side effects associated with antihypertensive drugs, the potential to prevent or reduce [BP] and therefore the risk of hypertension with vitamin D is very attractive,” Elina Hyppönen, PhD, from the University of South Australia, Adelaide, said in a press release.

The researchers conducted a Mendelian randomization study in which they generated a 25-hydroxyvitamin D, or 25-(OH)D, synthesis score based on variants of the CYP2R1 and DHCR7 genes, which affect 25-(OH)D synthesis or substrate availability and can be used as a proxy for 25-(OH)D concentration. They performed a meta-analysis of data for up to 108,173 people from 35 studies in the D-CarDia collaboration to determine associations between allele score and BP measurements. They also analyzed summary statistics from three consortia.

Reduced odds of hypertension

In phentotypic analyses conducted by the researchers (n=up to 49,363), increased 25-(OH)D concentration was associated with decreased systolic BP (beta per 10% increase, –0.12 mm Hg; 95% CI, –0.2 to –0.04) and lower odds of hypertension (OR=0.98; 95% CI, 0.97-0.99). The same trend was not observed with decreased diastolic BP (beta per 10% increase, –0.02 mm Hg; 95% CI, –0.08 to 0.03).

The researchers also combined data from D-CarDia and the International Consortium on Blood Pressure for a meta-analysis (n=146,581). In that analysis, each 25-(OH)D-increasing allele of the synthesis score was associated with a change in systolic BP of –0.1 mm Hg (95% CI, –0.21 to –0.0001) and a change in diastolic BP of –0.08 mm Hg (95% CI, –0.15 to –0.02).

In a meta-analysis combining D-CarDia and the consortia data (n=142,255), the synthesis score was linked to lower odds of hypertension (OR per allele=0.98; 95% CI, 0.96-0.99).

The researchers also determined in an instrumental variable analysis that each 10% increase in genetically instrumented 25-(OH)D concentration was linked to a change of –0.29 mm Hg in diastolic BP (95% CI, –0.52 to –0.07) and –0.37 mm Hg in systolic BP (95% CI, –0.73 to 0.003), as well as an 8.1% decrease in odds for hypertension (OR=0.92; 95% CI, 0.87-0.97).

“Mendelian randomization helps determine cause and effect because by using genetic data we can better avoid confounding, reverse causation and bias,” Hyppönen said in the release. “However, because we cannot exclude the possibility that our findings were caused by chance, they need to be replicated in an independent, similarly powered study. Further studies using randomized controlled trials are also needed to confirm causality and the potential clinical benefits of vitamin D supplementation.”

Important step

According to Shoaib Afzal, MD, PhD, from Copenhagen University Hospital, and Børge G. Nordestgaard, MD, DMSc, from the University of Copenhagen, Denmark, this study “is an important step toward delineation of the role of low vitamin D concentrations in the pathogenesis of hypertension,” they wrote in an invited commentary.

However, they wrote, more research is needed because, among other reasons, some of the P values in the study were close to .05, so random chance cannot be excluded. Also, the risk for stroke was not examined.

For more information:

Afzal S. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(14)70119-6.

Vimaleswaran KS. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(14)70113-5.

Disclosure: One researcher is an employee of GlaxoSmithKline and holds shares in the company, another serves on an advisory board for and has received research support from DiaSorin, and a third has received consulting honoraria from Eli Lilly. The other researchers, Afzal and Nordestgaard report no relevant financial disclosures.

New genetic research has identified a causal link between increased plasma concentrations of 25-hydroxyvitamin D and reduced risk for hypertension.

Previous data suggested that low levels of vitamin D are associated with increased risk for CVD and death, and ongoing trials are assessing whether vitamin D supplementation may attenuate that risk. However, a causal link between vitamin D levels and hypertension had not been demonstrated, according to the study background.

“In view of the costs and side effects associated with antihypertensive drugs, the potential to prevent or reduce [BP] and therefore the risk of hypertension with vitamin D is very attractive,” Elina Hyppönen, PhD, from the University of South Australia, Adelaide, said in a press release.

The researchers conducted a Mendelian randomization study in which they generated a 25-hydroxyvitamin D, or 25-(OH)D, synthesis score based on variants of the CYP2R1 and DHCR7 genes, which affect 25-(OH)D synthesis or substrate availability and can be used as a proxy for 25-(OH)D concentration. They performed a meta-analysis of data for up to 108,173 people from 35 studies in the D-CarDia collaboration to determine associations between allele score and BP measurements. They also analyzed summary statistics from three consortia.

Reduced odds of hypertension

In phentotypic analyses conducted by the researchers (n=up to 49,363), increased 25-(OH)D concentration was associated with decreased systolic BP (beta per 10% increase, –0.12 mm Hg; 95% CI, –0.2 to –0.04) and lower odds of hypertension (OR=0.98; 95% CI, 0.97-0.99). The same trend was not observed with decreased diastolic BP (beta per 10% increase, –0.02 mm Hg; 95% CI, –0.08 to 0.03).

The researchers also combined data from D-CarDia and the International Consortium on Blood Pressure for a meta-analysis (n=146,581). In that analysis, each 25-(OH)D-increasing allele of the synthesis score was associated with a change in systolic BP of –0.1 mm Hg (95% CI, –0.21 to –0.0001) and a change in diastolic BP of –0.08 mm Hg (95% CI, –0.15 to –0.02).

In a meta-analysis combining D-CarDia and the consortia data (n=142,255), the synthesis score was linked to lower odds of hypertension (OR per allele=0.98; 95% CI, 0.96-0.99).

The researchers also determined in an instrumental variable analysis that each 10% increase in genetically instrumented 25-(OH)D concentration was linked to a change of –0.29 mm Hg in diastolic BP (95% CI, –0.52 to –0.07) and –0.37 mm Hg in systolic BP (95% CI, –0.73 to 0.003), as well as an 8.1% decrease in odds for hypertension (OR=0.92; 95% CI, 0.87-0.97).

“Mendelian randomization helps determine cause and effect because by using genetic data we can better avoid confounding, reverse causation and bias,” Hyppönen said in the release. “However, because we cannot exclude the possibility that our findings were caused by chance, they need to be replicated in an independent, similarly powered study. Further studies using randomized controlled trials are also needed to confirm causality and the potential clinical benefits of vitamin D supplementation.”

Important step

According to Shoaib Afzal, MD, PhD, from Copenhagen University Hospital, and Børge G. Nordestgaard, MD, DMSc, from the University of Copenhagen, Denmark, this study “is an important step toward delineation of the role of low vitamin D concentrations in the pathogenesis of hypertension,” they wrote in an invited commentary.

However, they wrote, more research is needed because, among other reasons, some of the P values in the study were close to .05, so random chance cannot be excluded. Also, the risk for stroke was not examined.

For more information:

Afzal S. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(14)70119-6.

Vimaleswaran KS. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(14)70113-5.

Disclosure: One researcher is an employee of GlaxoSmithKline and holds shares in the company, another serves on an advisory board for and has received research support from DiaSorin, and a third has received consulting honoraria from Eli Lilly. The other researchers, Afzal and Nordestgaard report no relevant financial disclosures.

    Perspective
    Keith C. Ferdinand

    Keith C. Ferdinand

    There is definite scientific plausibility, based mainly on observational data, that low vitamin D levels are associated with, and even causal for, increased BP in susceptible individuals. This large, well-done study adds to the growing evidence that Mendelian randomization will accelerate our understanding of the pathogenesis of several chronic diseases, including hypertension. In this case, genetic variants associated with low endogenous production of 25-(OH)D have an increased risk for hypertension. 

    Nevertheless, the highest level of evidence would be an appropriately powered and correctly dosed intervention trial with vitamin D for hypertension treatment. Despite some success in recent studies with vitamin supplementation, the conclusive study remains elusive. Clinicians who seek to help their patients with hypertension now, especially darker-skinned individuals in northern latitudes, may consider checking vitamin D levels and intervening if suboptimal.

    • Keith C. Ferdinand, MD, FACC, FAHA
    • Professor of Clinical Medicine Tulane University, New Orleans Chair, National Forum for Heart Disease and Stroke Prevention

    Disclosures: Ferdinand reports no relevant financial disclosures.