Serum magnesium levels and risk of coronary artery disease: Mendelian randomisation study

Susanna C. Larsson, Stephen Burgess, Karl Michaëlsson

Observational studies have shown that serum magnesium levels are inversely associated with risk of cardiovascular disease, but whether this association is causal is unknown. We conducted a Mendelian randomisation study to investigate whether serum magnesium levels may be causally associated with coronary artery disease (CAD). This Mendelian randomisation analysis is based on summary-level data from the CARDIoGRAMplusC4D consortium's 1000 Genomes-based genome-wide association meta-analysis of 48 studies with a total of 60,801 CAD cases and 123,504 non-cases. Six single-nucleotide polymorphisms associated with serum magnesium levels at genome-wide significance were used as instrumental variables. A genetic predisposition to higher serum magnesium levels was inversely associated with CAD. In conventional Mendelian randomisation analysis, the odds ratio of CAD was 0.88 (95% confidence interval [CI] 0.78 to 0.99; P = 0.03) per 0.1-mmol/L (about 1 standard deviation) increase in genetically predicted serum magnesium levels. Results were consistent in sensitivity analyses using the weighted median and heterogeneity-penalised model averaging methods, with odds ratios of 0.84 (95% CI 0.72 to 0.98; P = 0.03) and 0.83 (95% CI 0.71 to 0.96; P = 0.02), respectively. This study based on genetics provides evidence that serum magnesium levels are inversely associated with risk of CAD. Randomised controlled trials elucidating whether magnesium supplementation lowers the risk of CAD, preferably in a setting at higher risk of hypomagnesaemia, are warranted.