Abstract 17045: Investigating the Causal Relationship Between Glycemic Trait and Great Vessels Structures Using Mendelian Randomization

Abstract

Introduction: Diabetes has been inversely associated with aortic aneurysm. However, it remains unclear whether this relationship is causal. In this study, we investigated the relationship between diabetes and glycemic traits, and MRI-derived measures of the great vessels (aortic and pulmonary artery) morphologies using Mendelian randomization (MR). Methods: We employed an inverse-variance weighted method to conduct a two-sample MR analysis using summary statistics from genome-wide association studies of glycemic traits (fasting insulin [FI], fasting glucose [FG], glycated hemoglobin [HbA1c], 2-hour glucose after oral challenge [2hGlu], and type 2 diabetes [T2D]) and MRI-derived measures of aortic morphology including ascending and descending aortic diameters (AAoD and DAoD), aortic distensibility (AoDist), aortic strain (AoStr), and pulmonary artery diameter (PAD). Sensitivity analysis was performed using the MR-Egger method, and pleiotropy was assessed using the MR-PRESSO method. Results: We observed evidence for associations between glycemic traits and aortic measures. Regarding aortic diameter, genetically predicted increases levels of 2hGlu, FG, and HbA1c were associated with decreased AAoD (2hGlu β = -0.11, p < 0.05; FG β = -0.15, p = 0.0002; HbA1c β = -0.18, p = 0.01) and DAoD (2hGlu β = -0.09, p < 0.001; FG β = -0.17, p = 0.0002; HbA1c β = -0.09, p = 0.02). No significant associations were observed between FI or T2D and both measures. We found that a genetically predicted increase in FI was associated with decreased AoStr (β = -0.23, p = 0.002) and AoDist (β = -0.18, p = 0.02), while a genetically predicted increase in HbA1c was associated with an increased AoStr (β = 0.18, p = 0.0008) and AoDist (β = 0.12, p = 0.03). Lastly, increased levels of FG and HbA1c were associated with an increase in PAD (FG β = 0.11, p = 0.02; HbA1C FG β = 0.25, p = 0.001). Conclusions: The genetic evidence supports the effects of glycemic traits on the aortic vasculature, providing additional causal evidence to support the epidemiological evidence linking high glucose exposure to aortic aneurysm. Further research is needed to better understand the mechanisms underlying these relationships.