A Prospective Study of Serum 25-Hydroxyvitamin D Levels and Mortality Among African Americans and Non-African Americans

Discussion

We observed that low serum levels of 25(OH)D were associated with an increased risk of subsequent mortality among African Americans and non-African Americans. Many reports have shown low 25(OH)D levels to be predictive of poor prognosis among seriously ill patients,^[28–32] but if causal, an association between vitamin D and mortality among normal middle-aged adults would have far more serious public health implications. To our knowledge, the only previous study to report African-American–specific results regarding vitamin D and total mortality was that by Melamed et al.^[11] within the Third National Health and Nutrition Examination Survey, which found no significant association with bottom quartile 25(OH)D levels (odds ratio = 1.05, 95% CI: 0.77, 1.44), although their analysis was based on only 401 African-American deaths and could not statistically distinguish these findings from the positive results among non-Hispanic whites. Nearly all previous epidemiologic studies of vitamin D and mortality have been conducted in populations entirely or largely of European descent (refer to reference 33 for review).^[19,20] Our study provides some of the first evidence that clinical vitamin D status may play an important role in mortality risk for African Americans, among whom vitamin D insufficiency is widespread.^[34]

To date, there are no published data from randomized controlled trials designed specifically to assess the effect of vitamin D supplementation on total mortality. However, Autier and Gandini^[35] conducted a mortality outcome meta-analysis of 18 trials involving subjects randomized to vitamin D supplementation for other endpoints, mainly bone mineral density or bone fractures. Although this analysis was limited in some respects by the design orientation of the original trials (e.g., by and large, the studies were conducted among frail, elderly individuals of European descent taking ordinary doses of vitamin D supplements often with the addition of calcium), they did report a significant 7% reduction in total mortality risk among vitamin D supplement users with a mean daily dose of 528 IU and a mean follow-up time of 5.7 years (range: from 6 months to 7 years).^[35] Among observational studies, several (including our own) are now in close accord in reporting an approximate doubling of mortality risk for 25(OH)D levels below ~10 ng/mL,^{[12,14,15,17]} and a recent meta-analysis of prospective observational studies with follow-up for overall mortality ranging from 1.3 to 13 years reported a summary relative risk for mortality of 0.77 (95% CI: 0.70, 0.84) associated with a 10-ng/mL increase in 25(OH)D over a median reference category of ~11 ng/mL.^[33] With 25(OH)D levels slowly decreasing in the adult US population,^[36] and with 21% of non-Hispanic whites and 73% of blacks currently estimated to have levels <20 ng/mL,^[34] these accumulating findings highlight the need to focus clinical attention on attaining adequate vitamin D levels.

Our findings may help to inform the current debate about the scope of the public health impact of vitamin D insufficiency and delineating "goal" levels of circulating 25(OH)D. Although an Institute of Medicine report recently classified serum 25(OH)D levels above 20 ng/mL as adequate,^[26] others have suggested values of 30 ng/mL or higher.^[1,27] Bischoff-Ferrari et al.^[37] have proposed that 25(OH)D levels of 36–40 ng/mL would be optimal with regard to several health endpoints, which corresponds well with our spline model predictions that the odds of mortality would minimize at 25(OH)D levels in the range of 35–40 ng/mL.

We did not find a significant inverse association between serum 25(OH)D and subsequent total cancer mortality, in agreement with some^[13,17,38] but not all^[18,39] observational studies. Randomized controlled trials of bone fractures have generally failed to detect significant benefits of vitamin D supplementation on total cancer mortality,^[40,41] and some recent analyses even suggested adverse effects on cancer mortality at high (>40 ng/mL) blood levels.^[18,38] Given the heterogeneous nature of cancer, grouping deaths across all cancer sites could obscure associations with specific cancers, but few studies have been sufficiently powered to examine cancer types individually for mortality. This may be resolved with ongoing follow-up of existing cohorts.

We found strong associations between baseline 25(OH)D and subsequent death from diseases of the circulatory system. This likely reflects contributions from multiple cardiovascular disease risk factors such as hypertension, atherosclerosis, inflammation, diabetes, and chronic kidney disease, all of which have been associated with vitamin D.^[8,42] Cells of vascular system tissue, including the heart, express the vitamin D receptor, and experimental data suggest that vitamin D receptor activation positively influences cardiovascular function through effects on vascular smooth muscle cell growth, fibrinolysis, inflammation, thrombogenicity, and endothelial regeneration.^[43–48] Calcitriol downregulates the renin-angiotensin system,^[49] and vitamin D receptor knockout mice develop phenotypes of hypertension, left ventricular hypertrophy, and enhanced thrombogenic activity.^[44,49] Similarly, human studies have shown that both ultraviolet B radiation and vitamin D supplementation may decrease blood pressure levels.^[50,51] Overall, experimental data reinforce mounting epidemiologic evidence of a link between vitamin D and cardiovascular dysfunction, incident cardiovascular events, and cardiovascular disease mortality.^[52–56]

Limitations of our study should be discussed. First, this is an observational study and not a randomized controlled trial and, thus, is susceptible to confounding influences that hinder causal inference. Second, the SCCS population is by design not representative of the general US population. The cohort is composed heavily of individuals of low socioeconomic status, having enrolled the vast majority of cohort members at community health centers that provide health services in medically underserved, low-income areas.^[23] However, this should not interfere with the validity of our internal analyses. Moreover, the sample of participants from which the cases and controls arose (i.e., the subset who provided baseline blood samples) is very similar with respect to age, education, income, body size, health habits (e.g., smoking), and medical history to that which did not provide a baseline blood sample (data not shown), so we can infer that our study sample is representative of the SCCS cohort. Third, we used only one 25(OH)D measurement as a proxy of "typical" vitamin D status, although we observed an intraclass correlation coefficient of 0.87 (95% CI: 0.83, 0.90) for serial measurements of 25(OH)D taken 1–3 years apart in a sample of more than 200 SCCS participants.^[57] Other groups have also found a single 25(OH)D measurement to adequately represent vitamin D status.^[58,59] Fourth, our data were too sparse at high levels of 25(OH)D to feasibly estimate an association with mortality at levels where adverse effects on disease and mortality have been reported.^[11,18,38] Finally, the available follow-up period was relatively short, and it will be of interest to determine whether our findings vary with extended follow-up. Of concern is the possibility that morbidity in the time period leading up to death would discourage outdoor (and thus sun) exposure, creating a reverse-causation bias. We took steps to mitigate this problem by restricting case selection to deaths that occurred after at least 1 year of follow-up. Subanalyses among deaths that occurred after 3.6 years (our average) of follow-up still showed a strong association with 25(OH)D: OR_Q3 = 1.15 (95% CI: 0.84, 1.58), OR_Q2 = 1.42 (95% CI: 1.04, 1.95), OR_Q1 = 1.64 (95% CI: 1.16, 2.30), similar for African Americans and non-African Americans. We also calculated the association between vitamin D and mortality among participants reportedly free of several chronic diseases at baseline and saw little effect on our results.

This investigation also has several notable strengths. To our knowledge, this study included the largest number of deaths of any single previous investigation of 25(OH)D and all-cause mortality. Further, unlike clinical populations, this community-based cohort allowed us to relate vitamin D status to subsequent mortality with findings of greater generalizability. Finally, we believe this represents the first robust assessment of the vitamin D–mortality association among African Americans, for whom vitamin D status has been a longstanding concern.

In conclusion, this study provides evidence that vitamin D status may have an important influence on mortality risk for African Americans and non-African Americans.

Am J Epidemiol. 2013;177(2):171-179. © 2013  Oxford University Press