Liver Enzymes and Risk of Ischemic Heart Disease and Type 2 Diabetes Mellitus: A Mendelian Randomization Study

We used Mendelian randomization to estimate the causal effects of the liver enzymes, alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT), on diabetes and cardiovascular disease, using genetic variants predicting these liver enzymes at genome wide significance applied to extensively genotyped case-control studies of diabetes (DIAGRAM) and coronary artery disease (CAD)/myocardial infarction (MI) (CARDIoGRAMplusC4D 1000 Genomes). Genetically higher ALT was associated with higher risk of diabetes, odds ratio (OR) 2.99 per 100% change in concentration (95% confidence interval (CI) 1.62 to 5.52) but ALP OR 0.92 (95% CI 0.71 to 1.19) and GGT OR 0.88 (95% CI 0.75 to 1.04) were not. Genetically predicted ALT, ALP and GGT were not clearly associated with CAD/MI (ALT OR 0.74, 95% CI 0.54 to 1.01, ALP OR 0.86, 95% CI 0.64 to 1.16 and GGT OR 1.08, 95% CI 0.97 to 1.19). We confirm observations of ALT increasing the risk of diabetes, but cannot exclude the possibility that higher ALT may protect against CAD/MI. We also cannot exclude the possibility that GGT increases the risk of CAD/MI and reduces the risk of diabetes. Informative explanations for these potentially contradictory associations should be sought.