We found in the general US population that 25(OH)D deficiency (the lowest quartile <17.8 ng/ml) was associated with a 26% higher risk of all-cause mortality, independent of baseline demographics, traditional and non-traditional CVD risk factors, and measures of a healthy lifestyle. The estimated association with increased risk of CVD mortality was similar, though of weaker statistical significance. We did not find an association with cancer mortality or other causes of death. This is the first study to our knowledge to explore the association between 25(OH)D levels and mortality in the general population.
Several lines of evidence suggest that vitamin D deficiency may be a risk factor for cardiovascular, cancer and all-cause mortality. Ecological studies reveal that CVD events are higher in the winter when vitamin D levels are lower33
and cancer survival is better if the cancer is diagnosed in the summer when vitamin D levels are higher34
. In addition, observational data shows that the use of activated vitamin D in patients with ESRD is associated with decreased mortality6-10
. Vitamin D receptor knock-out mice experience cardiac myocyte hypertrophy.2
Activated vitamin D has anti-proliferative properties5
. In mice, vitamin D is an inhibitor of the renin-angiotensin system1
. Other inhibitors of the renin-angiotensin system, such as ACE inhibitors, reduce mortality and morbidity in multiple disease states35
Low 25(OH)D levels are also associated with hypertension, diabetes mellitus, insulin resistance and an elevated BMI, all of which are risk factors for CVD and all-cause mortality. Low 25(OH)D levels12
, but not vitamin D intake36
, are associated with incident hypertension. There are two small clinical trials that suggest that vitamin D supplementation37, 38
reduced systolic BP. The association of 25(OH)D deficiency with obesity39, 40
, glucose intolerance15, 16, 41
, and the metabolic syndrome42
is another potential mechanism for increased CVD risk. We found that diabetes mellitus and increased BMI were independently associated with increased odds of being 25(OH)D deficient. We adjusted for hypertension, diabetes mellitus and BMI in our analyses and still found a significant association with all-cause mortality. Analyses with and without hypertension and diabetes mellitus in the model did not reveal a difference in the risk estimates associated with low 25(OH)D levels. However, this analysis did not account for incident diabetes and hypertension developing after the NHANES survey period.
The association of low 25(OH)D levels with mortality was strongest in those without CVD, without hypertension and without diabetes mellitus, arguing against low vitamin D levels being just a marker of poor general health. If diabetes mellitus and hypertension are in the causal pathway between low 25(OH)D levels and mortality, i.e. low 25(OH)D leads to hypertension which leads to higher mortality, it follows that the effect is more pronounced in those without pre-existing diabetes mellitus, hypertension and CVD. The fact that the associations were stronger in those without CVD at baseline suggests that if a causal relationship exists, 25(OH)D deficiency may play a role before CVD is established.
It is unclear why the association between 25(OH)D levels and mortality was more pronounced amongst women. It may be that there is a hormone interaction between estrogens and 25(OH)D. Women tend to develop atherosclerosis later in life compared to men suggesting that, similarly to the no CVD subgroup, perhaps low 25(OH)D levels play a role before the development of atherosclerosis. This area deserves further research and may help reveal the mechanisms behind the associations seen, if in fact they are causal.
A recently published randomized clinical trial of calcium and 400 IU/day vitamin D supplementation in generally healthy post-menopausal women did not show a lower risk of cardiovascular events in those randomized to vitamin D and calcium43
. However, a meta-analysis of 18 randomized clinical trials showed that participants randomized to vitamin D supplementation experienced fewer deaths compared to those randomized to placebo18
. In that analysis, as in ours, they were not able to establish the specific cause of death responsible for the lower mortality.
Several authors have commented that the optimal levels of 25(OH)D should be greater than 30 ng/ml19, 20
. In our observational study we found that there was a lower risk of mortality at levels 30-49 ng/ml but that at levels >50 ng/ml there was again a higher risk of mortality in women. This is similar to findings about anti-oxidant vitamins and vitamin E, which show that too much may be harmful44, 45
Several associations between vitamin D deficiency and clinical factors need further explanation. In adjusted analysis, low SES was associated with a lower risk of being 25(OH)D deficient. Most of the confounding was due to the very strong association between non-Hispanic black race and low 25-OH D status. The mechanism for the protective effect of low SES is unknown. However, one may conjecture that participants with low SES may spend more time outdoors and therefore have more sun exposure.
Our study is limited in that it is an observational study and therefore causality cannot be inferred. We adjusted for all known traditional CVD risk factors and non-traditional risk factors, including markers of a healthy lifestyle, such as the use of vitamin D supplementation. Residual confounding, however, may still exist. Specifically, the excess mortality observed in the lowest quartile may be a reflection of the participant's overall poor condition, or an unmeasured confounder, which we could not fully adjust for in our analysis. We were not able to distinguish the specific causes of mortality which accounted for the elevated all-cause mortality risk associated with 25(OH)D deficiency in our population, perhaps due to limitations of power or to the use of potentially imprecise death certificate data. Northern states were only sampled in the summer in NHANES III and therefore the full extent of 25(OH)D deficiency in the population is probably under-estimated. This probably attenuates the association seen in our results. Lastly, one must view the subgroup analyses with caution due to issues of multiple comparisons.
In conclusion, the lowest quartile of 25(OH)D (<17.8 ng/ml) is associated with a higher risk of all-cause mortality in the general US population. Further observational studies are needed to confirm these findings and establish the mechanisms underlying these observations. If confirmed, randomized clinical trials will be needed to determine whether vitamin D supplementation therapy at higher doses could have any potential benefit in reducing future mortality risk in those with 25(OH)D deficiency.