Genetic Variants in the Vitamin D Pathway, 25(OH)D Levels, and Mortality in a Large Population-Based Cohort Study

Context: Low 25-hydroxyvitamin D [25(OH)D] concentrations have been consistently associated with excess mortality in epidemiological studies, but this association could be due to confounding by health impairments associated with low 25(OH)D levels. An association of vitamin D–related genetic variants with all-cause mortality could strengthen the claims of causality, because this association is assumed to be unaffected by confounding. Objective: To assess the associations of low 25(OH)D with mortality in the presence or absence of genetic variants in the vitamin D pathway. Design, Setting, and Participants: The study consisted of a population-based cohort of 8417 German older adults in whom genetic variants were genotyped. Main Outcome Measures: The primary outcome measure was all-cause mortality. Results: Two single nucleotide polymorphisms (SNPs), rs3755967 (GC) and rs11603330 (DHCR7), were associated with higher risk of low vitamin D status [odds ratio (95% confidence interval) per minor allele, 1.27 (1.18 to 1.36) and 1.16 (1.08 to 1.25), respectively]. Low 25(OH)D (less than the season-specific 33rd percentile) was associated with increased mortality. However, none of the SNPs was associated with increased mortality. Furthermore, the increase in mortality for those with low 25(OH)D was generally smaller in the presence of the risk alleles for low 25(OH)D [“genetically low 25(OH)D”] than in the absence of those risk alleles [“otherwise low 25(OH)D”]. Conclusions: Although we may have been limited by a low statistical power to detect small associations, our study showed that the strong relationship between low 25(OH)D and increased mortality may be at least partly due to other factors related to low 25(OH)D levels.