Among 1,484 non-obese young women without hypertension, diabetes, or coronary disease at baseline, lower levels of plasma 25(OH)D levels independently predicted clinically important differences in the odds of subsequently developing hypertension. Furthermore, almost two thirds of the population had vitamin D deficiency; if this association were causal, then a substantial proportion of hypertension incidence among young women could be attributed to sub-optimal levels of 25(OH)D.
Cross-sectional observations support a relation between vitamin D and blood pressure. Older studies examined UVB radiation as a surrogate marker of vitamin D synthesis in the skin, which declines with increasing distance from the equator and is lower in the winter compared to summer.14
In the INTERSALT study, which examined over 10,000 participants from around the world, systolic and diastolic blood pressure were significantly and positively associated with distance from the equator.16, 17
Further evidence comes from geographical differences in blood pressure among individuals of African origin, with those residing in northern regions having higher blood pressure than those residing closer to the equator.18
Several studies have shown seasonal variations within the same population, with blood pressure peaking in winter and falling in summer.19, 20
More recently, in an analysis of the third National Health and Nutrition Examination Survey, the prevalence of hypertension was 30% higher among individuals in the lowest compared to highest quartile of 25(OH)D.22
Prospective studies of this association are few and small in size. For example, Kruse et al. randomized eighteen patients with mild hypertension to receive UVB exposure or UVA (ultraviolet A does not produce vitamin D) three times weekly for six weeks.21
Along with a 162% rise in plasma 25(OH)D in the UVB group, both systolic and diastolic blood pressure fell by 6 mmHg. No change was observed with UVA exposure.21
Another small interventional trial conducted in 148 vitamin D deficient elderly women demonstrated that 800 IU/d of oral vitamin D for six weeks lowered systolic blood pressure by 9.3%.23
In a prospective cohort study of older men and women we previously demonstrated that vitamin D deficient individuals had a 3.2-fold higher risk of hypertension incidence compared to those with optimal levels after adjusting for age, race, BMI, and physical activity; however, that study had limited statistical power (only 190 cases), and lacked measurement of other potential confounders such as PTH, renal function, and other circulating biomarkers.24
Several potential mechanisms for an association between 25(OH)D and hypertension have been suggested. First, Li et al. showed that 1,25(OH)2
D, the result of 1-hydroxylation of 25(OH)D, inhibits renin expression in mice.4
Second, lower levels of 25(OH)D are associated with insulin resistance,25
and vitamin D therapy may enhance insulin secretion and insulin sensitivity.11, 12
Insulin resistance has been proposed to be involved in the pathogenesis of hypertension.32
D inhibits growth of cultured VSMC in vitro
Thus the vitamin D - hypertension association may be mediated the renin-angiotensin system, insulin resistance, and vascular function.
Furthermore, the 1α-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2
D is expressed in a variety of tissues, including human endothelial cells, human VSMC, macrophages,5
and throughout the kidney.6-9
Therefore, 25(OH)D may have biologic effects that are independent of measurable circulating 1,25(OH)2
D levels; this challenges the traditional notion that biologic activity of vitamin D is primarily dependent upon conversion in the renal proximal tubule.
Our study has limitations that deserve mention. First, we relied on self-reported hypertension and did not directly measure the blood pressure of our participants; however, all participants are registered nurses, and we demonstrated that hypertension reporting by participants of this cohort is highly sensitive. Second, the specificity of hypertension reporting may have resulted in the misclassification of a few truly hypertensive individuals as being non-hypertensive controls; however, such misclassification would tend to diminish the magnitude of the odds ratio. Therefore, our findings may indeed be an underestimate of the true association. Third, we purposefully restricted our sample to women with BMI values < 30 kg/m2
. Although this limits the generalizability of our findings to non-obese women, obesity is such a powerful risk factor for both hypertension and reduced 25(OH)D levels, inclusion of a large number of obese women may have obscured a true association.30, 31
Fourth, we had a single measurement of 25(OH)D; because levels may fluctuate over time, longer periods of follow-up may result in more random misclassification. However, as with misclassification of hypertension status, this would tend to diminish the magnitude of the odds ratio, thereby underestimating the true association. Fifth, our study population was almost entirely white and, therefore, not necessarily generalizable to non-whites. Finally, we had insufficient power to demonstrate that the association between plasma 25(OH)D levels and incident hypertension differed according to vitamin D status (deficient vs. sufficient). Nevertheless, the shape of the association depicted in , as well as the lack of any association among women with sufficient vitamin D levels suggests a non-linear association.