Genetic evidence for lifestyle and cardiometabolic factors on the risk of aortic aneurysms: A comprehensive Mendelian randomization study

Background and aims: Aortic aneurysm (AAs) is a chronic and severe aortic disease, which is extremely life- threatening due to its delayed diagnosis and a high risk of rupture. In current studies, the association between lifestyle and metabolic factors remains controversial given the complexity of pathogenesis and progression in AAs. Consequently, more reliable and robust evidence should be provided. Methods: Genome-wide association studies summary statistics were obtained for 25 factors (6 lifestyle factors and 19 cardiometabolic factors) and AAs. Univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) were used to estimate the causal effect of these factors on AAs. Meanwhile, mediation analysis was applied to assess the mediated effect of lifestyle on the association of cardiometabolic factors with AAs. Results: Several factors were associated with AA risk, among which triglyceride (TG) (OR = 1.32, 95 % CI = [1.18-1.47], p <0.001) and high-density lipoprotein cholesterol (HDL-C) (OR = 0.70, 95 % CI = [0.61-0.82], p <0.001) remain consistently associated with AA risk, with an idependent effect on AAs after adjusting for body mass index (BMI). In addition, TG mediated 15.6 % of BMI effects and 3.7 % of smoking effects on AAs, and HDLC mediated 5.3 % of the effects of cigarette smoking on AAs. Conclusions: TG and HDL-C may be the most reliable factors in the risk of AAs. More scientific management of lifestyle and regular monitoring for cardiometabolic traits may serve as a new and effective direction for the prevention and control of the occurrence of AAs.