Vitamin D and Mortality: a Mendelian Randomization Study

Background: Decreased circulating 25-hydroxy-vitamin D (25-OH-vitamin D) concentrations have been associated with mortality rates, but it is unclear whether this association is causal. We performed a Mendelian randomization study and analyzed whether 3 common single-nucleotide polymorphisms (SNPs) associated with 25-OH-vitamin D concentrations are causal for mortality rates.

Methods: Genotypes of SNPs in the group-specific component gene (GC, rs2282679), 7-dehydrocholesterol reductase gene (DHCR7, rs12785878), and cytochrome P450 IIR-1 gene (CYP2R1, rs10741657) were determined in a prospective cohort study of 3316 male and female participants [mean age 62.6 (10.6) years] scheduled for coronary angiography between 1997 and 2000. 25-OH-vitamin D concentrations were determined by RIA. The main outcome measures were all-cause deaths, cardiovascular deaths, and noncardiovascular deaths.

Results: In a linear regression model adjusting for month of blood sampling, age, and sex, vitamin D concentrations were predicted by GC genotype (P < 0.001), CYP2R1 genotype (P = 0.068), and DHCR7 genotype (P < 0.001), with a coefficient of determination (r(2)) of 0.175. During a median follow-up time of 9.9 years, 955 persons (30.0%) died, including 619 deaths from cardiovascular causes. In a multivariate Cox regression adjusted for classical risk factors, GC, CYP2R1, and DHCR7 genotypes were not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality.

Conclusions: Genetic variants associated with 25-OH-vitamin D concentrations do not predict mortality. This suggests that low 25-OH-vitamin D concentrations are associated with, but unlikely to be causal for, higher mortality rates.