Effect of Glucagon on Ischemic Heart Disease and Its Risk Factors: A Mendelian Randomization Study

Context Glucagon acts reciprocally with insulin to regular blood glucose. However, the effect of glucagon on cardiovascular disease has not been widely studied. It has been suggested that insulin may increase the risk of ischemic heart disease. Objective To investigate whether glucagon, the main counteracting hormone of insulin, plays a role in development of ischemic heart disease. Design, Setting, and Participants In this 2-sample Mendelian randomization study, we estimated the causal effect of glucagon on ischemic heart disease and its risk factors using the inverse-variance weighted method with multiplicative random effects and multiple sensitivity analyses. Genetic associations with glucagon and ischemic heart disease and its risk factors, including type 2 diabetes and fasting insulin, were obtained from publicly available genome-wide association studies. Main Outcome Measure Odds ratio for ischemic heart disease and its risk factors per 1 standard deviation change in genetically predicted glucagon. Results Twenty-four single-nucleotide polymorphisms strongly (P < 5 × 10−6) and independently (r2 < 0.05) predicting glucagon were obtained. Genetically predicted higher glucagon was associated with an increased risk of ischemic heart disease (inverse-variance weighted odds ratio, 1.03; 95% confidence interval, 1.0003-1.05) but not with type 2 diabetes (inverse-variance weighted odds ratio, 0.998, 95% confidence interval, 0.97-1.03), log-transformed fasting insulin (inverse-variance weighted beta, 0.002, 95% confidence interval, -0.01 to 0.01), other glycemic traits, blood pressure, reticulocyte, or lipids. Conclusion Glucagon might have an adverse impact on ischemic heart disease. Relevance of the underlying pathway to existing and potential interventions should be investigated.