Genetic associations of ferroptosis-related eQTLs and immune cell phenotypes with aortic dissection risk: an integrative Mendelian randomization and single-cell analysis

Aortic dissection (AD) is a catastrophic vascular disorder. Although advancements in surgical procedures and endovascular techniques have improved the prognosis for patients with AD, the incidence and mortality rates remain relatively high. Recently, ferroptosis has been implicated in the occurrence and progression of AD. However, the association between ferroptosis and AD has yet to be conclusively established. We utilized a two-sample Mendelian randomization (MR) design to assess the genetic associations of ferroptosis-related gene eQTLs and 731 immune cell phenotypes (ICPs) with AD. Subsequently, we evaluated the mediating role of these ICPs in the genetic association between ferroptosis-related gene eQTLs and AD through mediation MR analysis. Finally, we performed single-cell RNA sequencing (scRNA-seq) analysis to assess the proportions and gene expression levels of the relevant immune cell subsets between controls and AD patients. MR analysis identified 40 ferroptosis-related gene eQTLs that were significantly linked to AD. Of these, 20 were associated with increased AD risk, while the remaining 20 were inversely associated with risk. Analysis revealed 33 ICPs associated with AD, with 18 classified as risk factors and 15 as protective factors. Mediation analysis suggested that CD14 on CD14 + CD16 − monocytes may mediate the genetic association between QSOX1, SRXN1, PCK2 and AD. Exploratory single-cell analysis revealed clear differences in monocyte composition and transcriptional profiles between controls and AD patients, and the expression pattern of QSOX1 was consistent with the mediation direction. This study used MR to identify ferroptosis-related gene eQTLs and ICPs associated with AD, with CD14 on CD14 + CD16 − monocytes showing a potential mediating role between ferroptosis-related gene eQTLs and AD. However, these findings are hypothesis-generating and require further validation through experimental studies and larger cohorts.