Circulating Protein Mediators Linking Genetically Predicted Smoking to Abdominal Aortic Aneurysm: A Genomic-Proteomic Analysis.

Background: Smoking is a well-established risk factor for abdominal aortic aneurysm (AAA). However, the molecular pathways underlying this relationship remain poorly understood. This study aimed to identify circulating protein mediators that may explain the association between smoking and AAA.

Methods: We conducted a network Mendelian randomization study using summary-level data from the largest available genome-wide association studies. Our primary smoking exposure was the lifetime smoking index, with smoking initiation and cigarettes per day included as supplementary traits. The AAA data set comprised 39 221 cases and 1 086 107 controls. Protein data were sourced from 2 large cohorts: UKB-PPP (the UK Biobank Pharma Proteomics Project), where proteins were measured using the Olink platform in 54 219 individuals, and deCODE, where proteins were measured using the SomaScan platform in 35 559 individuals. Two-sample Mendelian randomization was used to estimate the association between smoking and AAA (β_total) and between smoking and circulating protein levels (β₁). Summary data-based Mendelian randomization was then used to assess the association between smoking-related proteins and AAA risk (β₂). Mediation pathways were identified based on the directionality of effect estimates, and the corresponding mediation effects were quantified.

Results: Genetically proxied smoking traits were consistently associated with an increased risk of AAA. The lifetime smoking index was associated with the levels of 543 out of 5764 unique circulating proteins, with 470 of these associations replicated in supplementary analyses using additional smoking traits and protein sources. Among the smoking-related proteins, genetically proxied levels of 22 were associated with AAA risk. Eight mediation pathways were identified, with ADAMTS15 (a disintegrin and metalloproteinase with thrombospondin motifs 15), IL1RN (interleukin-1 receptor antagonist protein), MMP12 (matrix metalloproteinases 12), PGF (placental growth factor), PCSK9 (proprotein convertase subtilisin/kexin type 9), and UXS1 (UDP-glucuronic acid decarboxylase 1) representing key mediators.

Conclusions: This study identified numerous circulating proteins that are potentially causally linked to smoking, and 8 of these proteins were found to mediate the association between smoking and AAA risk.