Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study.

BACKGROUND: Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking. OBJECTIVE: To assess genetic evidence for the causal role of low vitamin D status in mortality. DESIGN: Nonlinear Mendelian randomization analyses. SETTING: UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010. PARTICIPANTS: 307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data. MEASUREMENTS: Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020. RESULTS: There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L. LIMITATIONS: Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate. CONCLUSION: Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels. PRIMARY FUNDING SOURCE: National Health and Medical Research Council.

Muscle Traits, Sarcopenia, and Sarcopenic Obesity: A Vitamin D Mendelian Randomization Study.

(1) Background: Observational studies associate vitamin D deficiency with muscle disorders, while some clinical trial data support a minor association between the vitamin and skeletal muscle performance in healthy subjects. Vitamin D receptor knockout mice studies confirm the relationship between vitamin D and skeletal muscle; however, causal inference in humans is challenging due to the ethical implications of including vitamin D-deficient participants in randomized trials. This study uses genetic methods to safely explore causal underpinnings for the relationship between 25(OH)D concentrations and skeletal muscle-related traits, including grip strength and combined arm skeletal muscle mass, and extends this analysis to suspected pathophysiology in the form of probable sarcopenia and sarcopenic obesity. (2) Methods: We conducted Mendelian randomization (MR) analyses in up to 307,281 participants from the UK Biobank of whom 25,414 had probable sarcopenia and 16,520 had sarcopenic obesity. In total, 35 variants were used to instrument 25(OH)D and MR analyses conducted using multiple approaches. (3) Results: Genetic analyses provided support for a relationship between genetically predicted higher 25(OH)D and skeletal muscle traits, with linear MR analyses for grip strength showing 0.11 kg (95% CI 0.04, 0.19) greater contractile force per 10 unit higher 25(OH)D, while there was a modest association with skeletal muscle mass (0.01 kg (95% CI 0.003, 0.02) greater muscle mass). For probable sarcopenia risk, there was suggestive evidence for lower odds by higher 25(OH)D (OR 0.96 (95% CI 0.92, 1.00)); however, this did not reflect an association with sarcopenic obesity (OR 0.97 (95% CI 0.93, 1.02)), but was seen in probable sarcopenia cases who were not obese (OR 0.92 (95% CI 0.86, 0.98)). Results were similar across multiple MR approaches. (4) Conclusions: Our study supports a causal relationship between 25(OH)D and skeletal muscle health. While evidence for benefit did not extend to lower risk of sarcopenic obesity, effective vitamin D-deficiency prevention strategies may help reduce age-related muscle weakness.

Differences and determinants of vitamin D deficiency among UK biobank participants: A cross-ethnic and socioeconomic study.

BACKGROUND: The public health relevance of true vitamin D deficiency is undisputed, although controversy remains regarding optimal vitamin D status. Few contemporary cross-ethnic studies have investigated the prevalence and determinants of very low 25-hydroxyvitamin D [25(OH)D] concentrations. METHODS: We conducted cross-ethnic analyses on the prevalence and determinants of vitamin D deficiency (25(OH)D ≤ 25 nmol/L) using data from 440,581 UK Biobank participants, of which 415,903 identified as White European, 7880 Asian, 7602 Black African, 1383 Chinese, and 6473 of mixed ancestry. Determinants of vitamin D deficiency were examined by logistic regression. RESULTS: The prevalence of vitamin D deficiency was highest among participants of Asian ancestry (57.2% in winter/spring and 50.8% in summer/autumn) followed by those of Black African ancestry (38.5% and 30.8%, respectively), mixed (36.5%, 22.5%), Chinese (33.1%, 20.7%) and White European ancestry (17.5%, 5.9%). Participants with higher socioeconomic deprivation were more likely to have 25(OH)D deficiency compared to less deprived participants (P = <1 × 10-300); this pattern was more apparent among those of White European ancestry and in summer (Pinteraction ≤6.4 × 10-5 for both). In fully-adjusted analyses, regular consumption of oily fish was associated with reduced odds of vitamin D deficiency across all ethnicities, while outdoor-time in summer was less effective for Black Africans (OR 0.89, 95% CI 0.70, 1.12) than White Europeans (OR 0.40, 95% CI 0.38, 0.42). CONCLUSIONS: Severe vitamin D deficiency remains an issue throughout the UK, particularly in lower socioeconomic areas. In some groups, levels of deficiency are alarmingly high with one-half of Asian and one-third of Black African ancestry populations affected across seasons. KEY MESSAGES: The prevalence of vitamin D deficiency in the UK is alarming, with certain ethnic and socioeconomic groups considered particularly vulnerable.