title: Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Despoina
authors.initials: D
authors.lastname: Manousaki
authors.affiliation: 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.).
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mokry
authors.affiliation: 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.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ross
authors.affiliation: 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.).
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: 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.). brent.richards@mcgill.ca.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
mesh_terms: D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000235:genetics*; D005787:Gene Frequency; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D057182:Mendelian Randomization Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D014808:Vitamin D Deficiency / Q000097:blood / Q000175:diagnosis / Q000235:genetics*
chemical_list: D015415:Biomarkers; D014807:Vitamin D; C104450:25-hydroxyvitamin D
keywords: Genome-Wide Association Study; Mendelian randomization analysis; coronary artery disease; single-nucleotide polymorphism; vitamin D