Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies

Abstract

Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, meta-analyses of RCTs that investigated the effect of vitamin D supplementation on multiple health outcomes, and MR studies that explored the causal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising 46 unique outcomes, and 73 MR studies comprising 43 unique outcomes were included in the present umbrella review. Twenty-eight disease outcomes were identified by both meta-analyses of observational studies and MR studies. Seventeen of these reported disease outcomes had consistent results, demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes.

Keywords: Mendelian randomization studies; meta-analysis; multiple health outcomes; observational studies; randomized controlled trials; umbrella review; vitamin D deficiency; vitamin D supplementation.

FIGURE 1

Flow diagram of the selection process. MR, Mendelian randomization; RCT, randomized controlled trial.

FIGURE 2

Flow chart of the study design.

FIGURE 3

Venn diagram of meta-analyses of observational studies, meta-analyses of RCTs, and MR studies. The plot was performed by R package “VennDiagram.” The number of disease outcomes for overlapping and distinct study types is shown. Ⅰ, only reported in MR studies; ⅠI, reported in MR studies and meta-analyses of RCTs; ⅠII, only reported in meta-analyses of RCTs; ⅠV, reported in all 3 study types; V, reported in MR studies and meta-analyses of observational studies; VI, reported in meta-analyses of RCTs and meta-analyses of observational studies; VII, only reported in meta-analyses of observational studies. MR, Mendelian randomization; RCT, randomized controlled trial.

FIGURE 4

Consistency between meta-analyses of observational studies, and MR studies for the same disease outcome. P is the P value in the test for interaction. MR, Mendelian randomization; RRR, ratio of relative risks.