Abstract P110: Proteomics Identified Novel Proteins Associated With Genetic Risk Of Abdominal Aortic Aneurysm: The Atherosclerosis Risk In Communities Study (ARIC)

Abstract

Introduction: Abdominal aortic aneurysm (AAA) is a condition characterized by a weakened dilated vessel wall with the potential for lethal rupture. A recent genome-wide association study identified and replicated nine AAA-related variants (rs602633, rs4129267, rs3827066, rs1795061, rs10757274, rs10985349, rs9316871, rs6511720, and rs2836411), but pathways through which these loci may influence disease have not been elucidated. Hypothesis: AAA risk variants were hypothesized to be associated with plasma proteins with numerous roles including, but not limited to, inflammation and extracellular matrix remodeling. Methods: Data from participants of the community-based ARIC Study were used. Genomic DNA from whole blood was genotyped using the Affymetrix Genome-Wide Human SNP array 6.0. Concentrations of 4,870 proteins were determined using the SomaLogic aptamer-based capture array in plasma collected at visit 3 (1993-95). Outliers that were 6 standard deviations from the means were excluded. Race-specific multiple linear regression analysis evaluated associations between genetic variants and log base 2 transformed protein levels, with adjustment for age, sex, estimated glomerular filtration rate, field center, and ten principal components of ancestry. Identified proteins in whites (N=7,241) were then examined for replication in Black participants (N=1,671). Cox regression was used to evaluate the associations between identified proteins and incident AAA (n=454) over a median 21.2-year follow-up in all 11,064 participants. Results: In white participants twenty-six protein associations were identified for rs602633 ( PSRC1-CELSR2-SORT1 ), rs4129267 ( IL6R ), and rs3827066 ( PCIF1-ZNF335-MMP9 ) following Bonferroni correction ( p ≤5.13x10 -6 ). Associations were observed between rs4129267 and soluble interleukin-6 receptor subunit alpha (β=-0.339; p<1.0E-200) and CRP (β=0.093; p=2.24E-7); rs602633 and granulin (β=0.184; p<1.0E-200), complement C1q TNF-related protein-1 (β=0.115; p=2.17E-184), and neogenin (β=-0.031; p=5.60E-13); and rs3827066 and kit ligand (β=-0.045; p=2.41E-08). Five associations were replicated in Black participants ( p ≤1.9x10 -3 ). In the whole cohort, top quintiles of CRP (HR: 1.68; 95% CI: 1.22, 2.31), kit ligand (HR: 0.56; 95% CI: 0.40, 0.78) and neogenin (HR: 0.57 95% CI: 0.42, 0.78) were significantly related to incident AAA risk compared to corresponding bottom quintiles. Conclusions: Three of the nine AAA risk variants were associated with plasma protein concentrations, with the strongest associations for those involved in inflammation, endothelial dysfunction, and extracellular matrix remodeling. Granulin, complement C1q tumor necrosis factor-related protein-1, kit ligand, and neogenin represent novel targets for genetic risk of AAA and may link genetic susceptibility to disease pathogenesis.