Vitamin D and high blood pressure: causal association or epiphenomenon?

Setor K. Kunutsor, Stephen Burgess, Patricia B. Munroe, Hassan Khan

High plasma levels of vitamin D are associated with a reduced risk of high blood pressure, but whether this association is causal remains to be ascertained. We performed a meta-analysis of randomized clinical trials, to examine the effect of vitamin D supplementation on both systolic blood pressure (SBP) and diastolic blood pressure (DBP) and supplemented these results with a Mendelian randomization analysis to investigate the causal relationship between vitamin D status (25-hydroxyvitamin D [25(OH)D]) and BP. Pooled random effects meta-analysis of weighted mean differences across 16 trials of vitamin D supplementation showed a non-significant reduction in SBP (-0.94, 95% CI -2.98, 1.10 mmHg) and DBP (-0.52, 95% CI -1.18, 0.14 mmHg), with evidence of heterogeneity (I(2) = 67.9%, P < 0.001) and publication bias (P = 0.02) among trials of SBP. There was a significant reduction in DBP (-1.31, 95% CI -2.28, -0.34 mmHg, P = 0.01) in participants with pre-existing cardiometabolic disease. Variants at three published loci (GC, DHCR7, CYP2R1, and CYP24A1) for 25(OH)D, were not significantly associated with BP, but rs6013897 in CYP24A1 gene region had nominally significant associations with both SBP and DBP (P < 0.05). Evidence from the associations of the genetic variants with the risk of vitamin D deficiency (defined as a 25(OH)D level < 50 nmol/L) and BP showed that the causal effects of a doubling of genetically-elevated risk of vitamin D deficiency were 0.14 mmHg (95% CI -0.19, 0.47, P = 0.42), and 0.12 mmHg (95% CI -0.09, 0.33, P = 0.25) on SBP and DBP respectively. Additional evidence from genetic data are directionally consistent with clinical trial data, though underpowered to reliably demonstrate a strong causal effect of vitamin D status on BP. Further investigation may be warranted.