Ng JCM, et al. - This two-sample Mendelian randomization study was undertaken to determine if glucagon, the main counteracting hormone of insulin, plays a role in development of ischemic heart disease. Using the inverse-variance weighted method with multiplicative random effects and multiple sensitivity analyses, the causal effect of glucagon on ischemic heart disease and its risk factors were estimated. Genetic associations with glucagon and ischemic heart disease and their risk factors, including type 2 diabetes and fasting insulin, were reported from genome-wide association studies which were publicly available. According to results, 24 single-nucleotide polymorphisms have been obtained which predict glucagon strongly and independently. Glucagon may adversely affect ischemic heart disease. It is worth exploring the importance of the underlying pathway to current and future interventions.