• Circ Cardiovasc Genet · Aug 2016

    Meta Analysis

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

    • Despoina Manousaki, Lauren E Mokry, Stephanie Ross, David Goltzman, and J Brent Richards.
    • From the Department of Epidemiology, Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada (D.M., L.E.M., S.R., J.B.R.); Departments of Medicine (D.G., J.B.R.) and Human Genetics (J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom (J.B.R.).
    • Circ Cardiovasc Genet. 2016 Aug 1; 9 (4): 349-56.

    BackgroundObservational 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 ResultsIn 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.ConclusionsGenetically 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.© 2016 American Heart Association, Inc.

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