Genetic variants in the vitamin D pathway, 25(OH)D levels, and mortality in a large population-based cohort study

摘要

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 going along 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: A population-based cohort of German men and women. Data from 8,417 participants with complete follow-up for mortality. Six genetic variants were genotyped. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: Two SNPs, rs3755967 (GC) and rs11603330 (DHCR7), were associated with higher risk of low vitamin D status (OR per minor allele, 95% CI: 1.27, 1.18-1.36 and 1.16, 1.08-1.25, respectively). Low 25(OH)D (below the season-specific 33rd percentile) was associated with increased all-cause, cardiovascular and cancer mortality. However, none of the SNPs were associated with increased mortality. Furthermore, the increase in mortality for those with low 25(OH)D was mostly 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 with low 25(OH)D levels.