Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts.
Level 3 - non-randomized controlled study
Mendelian randomization analysis within prospective cohort studies.
PubMed 25406188 · doi:10.1136/bmj.g6330
What was done
A Mendelian randomization and observational cohort analysis was conducted across three Danish cohorts (Copenhagen City Heart Study, Copenhagen General Population Study, and Copenhagen Ischemic Heart Disease Study) comprising 95,766 white individuals of Danish descent followed through 2013 (median follow-up 5.8 to 19.1 years). Genotypes for variants in DHCR7 and CYP2R1 were analyzed; 35,334 participants also had measured plasma 25-hydroxyvitamin D concentrations. Primary outcomes were all-cause and cause-specific mortality (10,349 total deaths).
What was found
Observationally, a 20 nmol/L lower plasma 25-hydroxyvitamin D concentration was associated with higher all-cause mortality (HR 1.19, 95% CI 1.14 to 1.25), cardiovascular mortality (HR 1.18, 95% CI 1.09 to 1.28), cancer mortality (HR 1.12, 95% CI 1.03 to 1.22), and other mortality (HR 1.27, 95% CI 1.15 to 1.40). Genetically, each DHCR7/CYP2R1 allele score increase decreased plasma 25-hydroxyvitamin D by 1.9 nmol/L. Genetically determined 20 nmol/L lower plasma concentrations were associated with increased odds of all-cause mortality (OR 1.30, 95% CI 1.05 to 1.61), cancer mortality (OR 1.43, 95% CI 1.02 to 1.99), and other mortality (OR 1.44, 95% CI 1.01 to 2.04), but not cardiovascular mortality (OR 0.77, 95% CI 0.55 to 1.08).
Why it matters
These genetic findings support a potential causal link between lifelong low vitamin D status and increased risk of cancer and all-cause mortality, while suggesting that the observational link between low vitamin D and cardiovascular death is likely confounded.
Limits
The study sample was entirely white Danish adults, limiting generalizability to other ethnicities and latitudes. Instrumental variables were limited to DHCR7 and CYP2R1 variants, and Mendelian randomization assumptions regarding pleiotropy cannot be fully ruled out from the abstract alone.
Cited by
- supports Mendelian randomization meta-analyses demonstrate that genetic single nucleotide polymorphisms causing lower circulating 25-hydroxyvitamin D levels are associated with significantly increased respiratory tract infection mortality, cancer mortality, and all-cause mortality, but not cardiovascular mortality.