Genetic evidence linking type 2 diabetes, circulating lactate and aortic dissection: a two- step Mendelian randomization study

Background: Diabetes has been associated with a lower risk of aortic dissection in several observational and genetic studies, but the mechanisms underlying this paradoxical association remain uncertain. Lactate is a diabetes-related metabolic intermediate with emerging links to vascular remodeling and aortic wall injury. We investigated whether circulating lactate contributes to the genetic association between diabetes and aortic dissection. Methods: We performed bidirectional two-sample Mendelian randomization using summary-level genome-wide association study data from European-ancestry populations. Genetic instruments were selected for type 1 diabetes, type 2 diabetes and circulating lactate. Aortic dissection was analyzed as the outcome. The inverse-variance weighted method was the primary estimator, with MR-Egger regression, weighted median, simple mode and weighted mode analyses used for sensitivity assessment. Heterogeneity, horizontal pleiotropy and single-instrument influence were evaluated using Cochran's Q statistic, MR-Egger intercept, MR-PRESSO and leave-one-out analyses. A two-step Mendelian randomization framework was used to estimate the lactate-mediated component of the type 2 diabetes and aortic dissection association. Results: Genetically predicted type 2 diabetes was inversely associated with aortic dissection risk (inverse-variance weighted odds ratio 0.749, 95% confidence interval 0.568 to 0.987; P = 0.040) and positively associated with circulating lactate (odds ratio 1.032, 95% confidence interval 1.010 to 1.054; P = 0.0039). Genetically predicted higher lactate was associated with increased aortic dissection risk (odds ratio 4.520, 95% confidence interval 1.711 to 11.942; P = 0.0023). Two-step mediation analysis indicated a suppressor-type indirect pathway through lactate, corresponding to a mediated proportion of -28.2%. Type 1 diabetes showed an inverse association with aortic dissection, but no lactate-mediated pathway was detected. Conclusions: This Mendelian randomization study supports an inverse genetic association between type 2 diabetes liability and aortic dissection, while identifying lactate as a genetically supported risk-related pathway that may counteract part of this association. The findings should be interpreted as genetic epidemiological evidence and require validation in independent clinical cohorts and experimental models.