Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study.
Level 3 - non-randomized controlled study
Nonlinear Mendelian randomization study within a prospective cohort
PubMed 36279545 · doi:10.7326/M21-3324
What was done
Researchers conducted a nonlinear Mendelian randomization study using 35 confirmed genetic variants for 25-hydroxyvitamin D (25-(OH)D) in 307,601 unrelated UK Biobank participants of White European ancestry (recruited 2006–2010, aged 37–73 years) with available genetic and 25-(OH)D data. All-cause and cause-specific (cardiovascular disease, cancer, and respiratory) mortality were tracked over up to 14 years of follow-up (to June 2020).
What was found
Across 18,700 recorded deaths, the association between genetically predicted 25-(OH)D and all-cause mortality was L-shaped (P for nonlinearity < 0.001), with mortality risk decreasing steeply as concentrations increased up to 50 nmol/L. Significant associations were also found for cancer, CVD, and respiratory mortality (P <= 0.033 for all). Participants with a measured 25-(OH)D concentration of 25 nmol/L had an estimated 25% higher odds of all-cause mortality compared with those at 50 nmol/L (odds ratio 1.25, 95% CI 1.16 to 1.35).
Why it matters
This study provides genetic evidence supporting a causal relationship between vitamin D deficiency and mortality, indicating that risk reduction is concentrated in correcting deficiency below 50 nmol/L rather than increasing levels across the entire population.
Limits
The study was restricted to participants of White European ancestry, limiting generalizability to other racial and ethnic groups. In addition, Mendelian randomization estimates provide proof-of-principle evidence for causality, but the exact quantitative strength of the association remains approximate.
Cited by
- supports Mendelian randomization studies show that genetically predicted low vitamin D levels are linked to higher all-cause mortality and approximately 25% higher respiratory disease mortality.