Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease

Abstract

Given this uncertainty, clinical practice guidelines do not support vitamin D supplementation for CAD risk reduction andBackground-Observational studies support a possible association between decreased vitamin D levels and risk of coronary artery disease (CAD); however, it remains unclear whether this relationship is causal. We aimed to evaluate whether genetically lowered vitamin D levels influence the risk of CAD using a Mendelian randomization approach. Methods and Results-In this 2-stage Mendelian randomization study, we first identified single-nucleotide polymorphisms associated with 25-hydroxyvitamin D (25OHD) levels in the SUNLIGHT consortium (n=33 996), then tested them for possible violation of Mendelian randomization assumptions. A count of risk alleles was tested for association with 25OHD levels in a separate cohort (n=2347). Alleles were weighted by their relative effect on 25OHD and tested for their combined effect on CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study (22 233 cases/64 762 controls). Four single-nucleotide polymorphisms were identified to be associated with 25OHD levels, all in or near genes implicated in 25OHD synthesis, transport or metabolism. A count of these risk alleles was strongly associated with 25OHD (n=2347, F-test statistic=49.7, P=2×10 −12). None of the single-nucleotide polymorphisms associated with 25OHD levels were associated with CAD (all P values >0.6). The Mendelian randomization odds ratio (OR) for CAD was 0.99 (95% confidence interval, 0.84-1.17; P=0.93; I 2 =0) per SD decrease in log-transformed 25OHD levels. These results persisted after sensitivity analyses for population stratification and pleiotropy. Conclusions-Genetically lowered 25OHD levels were not associated with increased risk of CAD in a large, well-powered study, suggesting that previous associations between circulating 25OHD levels and CAD are possibly confounded or due to reverse causation. (Circ Cardiovasc

Metabolic profiling–multitude of technologies with great research potential, but (when) will translation emerge?

“…The study findings suggested that associations between schizophrenia and 25-hydroxyvitamin D may not be causal, and, therefore the evidential basis for vitamin D supplementation as a candidate approach for preventing schizophrenia is weakened. Similarly, a recent extensive Mendelian randomization study provides no support for a causal role for 25-hydroxyvitamin D in the risk of coronary artery disease 55 . On the other hand, in this issue Ong and co-workers 56 found that genetically lowered 25-hydroxyvitamin D levels were associated with higher susceptibility to ovarian cancer.…”

Vitamin D Deficiency and Cardiovascular Diseases

“…With respect to hypertension, Vimaleswaran et al 66 found that increased vitamin D levels could reduce the risk of development of CVD, showing a causal relationship. 66 On the other hand, the results of MR studies have not demonstrated a causal relationship for diabetes mellitus 67 and CAD, 68 in which vitamin D deficiency appears to be a confounding factor.…”

Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease

“…Our findings suggest that previously observed associations are very likely to be confounded by CHD risk factors and lifestyle variables associated with 25OHD. In support of this notion, by using Mendelian randomization approach and eliminating confounding, genetically determined 25OHD was not found to be associated with risk of incident CHD 21 or cardiovascular mortality 22 . Therefore, the causality and the effects of vitamin D supplement on CHD are yet to be clarified in ongoing and future randomized controlled trials.…”