Differentiating Associations of Glycemic Traits with Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation

 We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher genetically-predicted glycemic traits were consistently associated with an increased risk of coronary atherosclerosis related diseases and symptoms. Genetically-predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically-predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically-predicted FG and 2hGlu were positively associated with the risk of large artery stroke. Genetically-predicted 2hGlu levels showed positive associations with the risk of small vessel stroke. Higher levels of genetically-predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically-predicted levels of 2hGlu and FI remained after adjusting for other glycemic traits. Increased glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis, but not thrombosis.