1. In this cohort study, low vitamin D measured at baseline was associated with an increased risk of death in adults.

2. Nonlinear Mendelian randomization analyses supported causal relations between low vitamin D and increased risk of death.

Evidence Rating Level: 2 (Good)

Study Rundown: Low vitamin D is associated with increased mortality, but studies of vitamin D supplementation in deficient participants are lacking. Vitamin D is predominantly derived from exposure to ultraviolet radiation from the sun. New research methods, such as nonlinear Mendelian randomization analyses, allow causal conclusions with observational data by incorporating genetic variants to reduce unmeasurable confounders. The present cohort study evaluated the association between measured baseline vitamin D levels and all-cause and cause-specific mortality. 25-(OH)D was measured as a marker of nutritional vitamin D status. Cause-specific mortality included respiratory, cancer, and cardiovascular disease. The total follow-up duration was 14 years. There was a nonlinear, inverse relationship between measured 25-(OH)D and mortality. Genetically predicted 25-(OH)D levels had an L-shaped association with all-cause, cancer, and cardiovascular mortality. As a limitation, the study did not use randomized control studies to support causal conclusions. The primary analysis was also limited to participants with a White European ancestry, which reduces generalizability to other populations.

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In-Depth [retrospective cohort]: The present study used data from the United Kingdom Biobank to evaluate the association between 25-(OH)D and mortality. This study also used nonlinear Mendelian randomization analyses to estimate the causal relationship using observational data and participant genetic variants. The primary analysis used data from unrelated participants of White European ancestry with measurements of serum 25-(OH)D concentration (n = 307,601). The follow-up period was 14 years. The Mendelian randomization analyses used genetically predicted concentrations of 25-(OH)D derived from a weighted genetic score of 35 autosomal single-nucleotide polymorphisms associated with measured 25-(OH)D concentrations. During the study, 18,700 deaths occurred. A higher mean of measured 25-(OH)D concentration was observed in participants with higher physical activity, higher socioeconomic status, lower body mass index, and who were nonsmokers. There was a nonlinear inverse relationship between measured 25-(OH)D and all-cause and cause-specific mortality. The largest difference in mortality risk was observed in the lowest quartile of 25-(OH)D concentration of 25 nmol/L compared to 50 nmol/L (Odds Ratio [OR], 1.36; 95% Confidence Interval [CI], 1.33 to 1.40). Genetically predicted 25-(OH)D had a nonlinear L-shaped association with all-cause (p<0.001), cancer, and cardiovascular mortality (p≤0.033). There was no association between genetically predicted 25-(OH)D and respiratory disease mortality. This is the first study to use nonlinear Mendelian randomization analyses to understand the causal relationship between vitamin D and mortality.

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