Abstract 16668: Serum Gamma Glutamyl Transferase and Risk of Coronary Artery Disease: A Causal Assessment by Mendelian Randomization
Background: Gamma glutamyl transferase (GGT) is a ubiquitous cell-surface enzyme that mediates oxidative stress and is elevated in persons with hepatic steatosis. Observational data have suggested a positive association between GGT and incident coronary artery disease (CAD), although the potential causal nature of this association remains unexplored.
Objective: To determine whether serum levels of GGT are causally associated with incident CAD by using a genetic instrument exclusively associated with serum GGT.
Methods: A meta-analysis was conducted of studies assessing the association between serum GGT and incident CAD, defined as CAD-related death, non-fatal MI, coronary artery bypass graft surgery and angioplasty. In addition, 26 single nucleotide polymorphisms (SNPs) associated with GGT at a genome wide significance level (p<5x10-8) were evaluated for pleiotropy against a panel of 25 vascular and non-vascular risk factors in publicly available databases and the Pakistan Risk of Myocardial Infarction Study (PROMIS). SNPs exclusively associated with serum GGT were combined to create a genetic risk score, which was further used to assess causality in 60,919 CAD cases and 80,243 controls from the CARDIoGRAMplusC4D consortium and the PROMIS study.
Results: In a meta-analysis of seven studies (total N = 1,111,751; total incident cases = 16,092), higher serum GGT was significantly associated with an increased risk of incident CAD (OR 1.44; 95% CI: 1.09-1.89; top v. bottom quintile). Of the 26 SNPs assessed, pleiotropic analysis identified 17 GGT-specific SNPs, which were combined to create a genetic risk score for causal assessment. Genetically-raised serum GGT levels were not significantly associated with incident CAD (OR 1.00; 95% CI: 0.99-1.00).
Conclusions: Higher levels of serum GGT are associated with increased risk of incident CAD, although the association does not appear to be causally mediated.
- © 2013 by American Heart Association, Inc.