Abstract Body: Introduction: Abdominal aortic aneurysm (AAA), characterized as bulging of the abdominal aorta, is life-threatening when it ruptures. While genetic susceptibility is a known risk factor for AAA, novel mechanisms associated with genetic risk have yet to be explored. This study aims to investigate the associations between the plasma proteome and genetic susceptibility for AAA, measured through a polygenic risk score (PRS).

Methods: We constructed a PRS for AAA for participants in the ARIC Study, an ongoing community-based prospective cohort, based on summary statistics from a recent genome-wide association study (GWAS) for AAA (PMID: 37845353). Applying Bayesian regression with continuous shrinkage priors, we calculated the PRS for each participant using SNP dosages available from ARIC and genome-wide SNP weights from the AAA GWAS.

We included 8978 European American (EA) participants as the discovery sample (52.9% female, mean age = 57.2) and 2672 African American (AA) participants as the replication (62.9% female, mean age= 56.3) sample. We measured plasma levels for 4955 proteins by SOMA scan v4 from samples collected at ARIC visit 2. We performed linear regression to evaluate the relationship between the AAA PRS and each of the 4955 plasma proteins, controlling for potential confounders. We used the following strategy to interpret PRS-protein associations in the discovery in EAs: Priority 1: 118 proteins that were previously associated with individual AAA risk variants in ARIC (PMID: 36579647); Priority 2: agnostic scan among the remaining 4837 proteins. Bonferroni correction for multiple testing was applied to the two groups of proteins separately in EAs. Uncorrected p<0.05 was applied in AAs.

Results: In EA participants, 8 proteins were associated with the AAA PRS among the 118 priority proteins (p < 4.24 * 10^-4) and 1 protein was associated with the AAA PRS in the agnostic scan of the remaining proteins (p < 1.03 * 10^-5), for a total of 9 significant proteins: S100A13, TBCA, LRRN1, CRIP1, IL6R, PLA2G7, C5orf38, PCDHB10, and MMP12. Of the 9 proteins, IL6R was replicated in AA participants (p<0.05) with the consistent direction of association.

Conclusion: Identifying the circulating proteomics signature for genetic susceptibility of AAA can further our understanding of AAA etiology and provide valuable insights into robust target interventions in preventing AAA.