Mendelian randomization suggests a causal link between glycemic traits and thoracic aortic structures and diseases

ImportanceType 2 diabetes mellitus (T2DM) and elevated glucose levels have been inversely associated with aortic aneurysms. However, the causality of this relationship remains uncertain. Additionally, there is a lack of studies investigating the association between glycemic traits and imaging-based thoracic aortic phenotypes. ObjectiveWe investigated whether T2DM and glycemic measures (fasting glucose (FG), fasting insulin (FI), glycated hemoglobin (HbA1c), and 2-hour post-load glucose (2hPG)) are causally associated with various imaging and clinical thoracic aortic phenotypes. Design, setting, and participantsWe performed Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies of glycemic traits (GT) and aortic phenotypes. We employed a two-sample univariate MR (UVMR) followed by a multivariable MR and MR analysis using a cluster-based approach. Main Outcomes and MeasuresThe outcome includes imaging-based ascending and descending aortic diameters (AAoD and DAoD), aortic distensibility (AoDist) and strain (AoStr), and thoracic aortic aneurysm and dissection (TAAD). The GT include FI, FG, HbA1c, 2hPG and T2DM. ResultsWe observed an inverse association between 2hPG, FG, HbA1c, and T2DM and AAoD, DAoD. For instance, the genetically predicted increases levels of 2hPG, FG, HbA1c, and T2DM were associated with decreased AAoD (2hPG {beta}= -0.2, p=3x10-08; FG {beta}= -0.21, p=5x10-05; HbA1c {beta}= -0.36, p=2x10-07; T2DM {beta}=-0.04, p=2x10-04) and reduce risk TAAD (2hPG decreased TAAD (2hPG OR= 0.70, p=4x10-04; FG OR= 0.58, p=3x10-05; HbA1c OR= 0.62, p=5x10-03; T2DM OR= 0.90, p=6x10-6). Further investigation showed that the inverse association between T2DM and aortic phenotypes is driven by genetic predictors of T2DM beta cell proinsulin clusters. UVMR and Proteomic MR showed a strong association with aortic phenotypes for genes, such as AGER, GLRX, TCF7L2, and GCK, which are known to play an important role in glucose regulation. Conclusion and relevanceOur findings suggest a potentially causal impact of GT on the aortic vasculature. Furthermore, specific glucose regulation genes such as GCK, AGER, and TCF7L2 appear to contribute to this process, opening avenues for potentially leveraging the druggability of these genes for treatment or preventions of TAAD.