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

Despoina Manousaki; Lauren E Mokry; Stephanie Ross; David Goltzman; J Brent Richards

doi:10.1161/CIRCGENETICS.116.001396

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

Circ Cardiovasc Genet. 2016 Aug;9(4):349-56. doi: 10.1161/CIRCGENETICS.116.001396. Epub 2016 Jul 14.

Authors

Despoina Manousaki¹, Lauren E Mokry¹, Stephanie Ross¹, David Goltzman¹, J Brent Richards²

Affiliations

¹ 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.).
² 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.

PMID: 27418593
DOI: 10.1161/CIRCGENETICS.116.001396

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.

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.

Keywords: Genome-Wide Association Study; Mendelian randomization analysis; coronary artery disease; single-nucleotide polymorphism; vitamin D.

Publication types

Meta-Analysis

MeSH terms

Biomarkers / blood
Case-Control Studies
Coronary Artery Disease / diagnosis
Coronary Artery Disease / genetics*
Gene Frequency
Genetic Pleiotropy
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Mendelian Randomization Analysis*
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide*
Risk Assessment
Risk Factors
Vitamin D / analogs & derivatives*
Vitamin D / blood
Vitamin D / genetics
Vitamin D Deficiency / blood
Vitamin D Deficiency / diagnosis
Vitamin D Deficiency / genetics*

Substances

Biomarkers
Vitamin D
25-hydroxyvitamin D