Circulating inflammatory proteins and abdominal aortic aneurysm: A two-sample Mendelian randomization and colocalization analyses.

ABSTRACT

OBJECTIVES: Inflammatory proteins are implicated in the progression of abdominal aortic aneurysms (AAA); however, it remains debated whether they are causal or consequential. This study aimed to assess the influence of circulating inflammatory proteins on AAA via two-sample Mendelian randomization (MR) and colocalization analysis. METHODS: Summary data on 91 circulating inflammatory protein levels were extracted from a comprehensive protein quantitative trait loci (pQTL) study involving 14,824 individuals. Genetic associations with AAA were derived from the FinnGen study (3,869 cases and 381,977 controls). MR analysis was conducted to assess the relationships between proteins and AAA risk. Colocalization analysis was employed to explore potential shared causal variants between identified proteins and AAA. RESULTS: Using a two-sample bidirectional MR study, our findings suggested that genetically predicted elevated levels of TGFB1 (OR = 1.21, P = 0.003), SIRT2 (OR = 1.196, P = 0.031) and TNFSF14 (OR = 1.129, P = 0.034) were linked to an increased risk of AAA. Conversely, genetically predicted higher levels of CD40 (OR = 0.912, P = 0.049), IL2RB (OR = 0.839, P = 0.028) and KITLG (OR = 0.827, P = 0.008) were associated with a decreased risk of AAA. Colocalization analyses supported the association of TGFB1 and SIRT2 levels with AAA risk. CONCLUSIONS: The proteome-wide MR and colocalization study identified TGFB1 and SIRT2 as being associated with the risk of AAA, warranting further investigation as potential therapeutic targets.