Abstract 1009: Elevated Lipoprotein (a) Is Associated With Increased Risk Of Abdominal Aortic Aneurysm.

Introduction: Lipoprotein(a) (Lp(a)) is an apolipoprotein B (ApoB) containing particle that is causally associated with atherosclerotic vascular disease and the target of emerging therapeutics. Recent work has highlighted the role of circulating lipoproteins in abdominal aortic aneurysm (AAA). We sought to triangulate human observational and genetic evidence to evaluate the role of Lp(a) in AAA. Methods: We tested the association between levels of Lp(a) and clinically diagnosed aortic aneurysms while controlling for traditional AAA risk factors and levels of ApoB using logistic regression among 798 individuals with and 384,499 individuals without AAA in the UK biobank (UKB). Multivariable Mendelian randomization (MVMR) was used to test for putatively casual associations between Lp(a) and AAA controlling for ApoB. Genetic instruments for Lp(a) and ApoB were created from genome-wide association studies (GWAS) of Lp(a) and ApoB comprising 335,796 and 418,505 UKB participants, respectively. The instruments were tested against AAA using data from a GWAS of 39,221 individuals with and 1,086,107 without AAA. Results: Elevated Lp(a) levels were associated with an increased risk of AAA (OR 1.04 per 10 nmol/L Lp(a); 95%CI 1.02-1.05; P150nmol/L) were likewise associated with an increased risk of AAA (OR 1.50; 95%CI 1.17-1.91; P<0.01) when compared to individuals with Lp(a) levels <150nmol/L. MVMR confirmed a significant association between genetically proxied increased Lp(a) and increased genetic liability to AAA (OR 1.13 per SD increased in Lp(a); 95%CI 1.02-1.24; P<0.02). Conclusion: Both observational and genetic casual inference analyses support an association between increased Lp(a) and AAA risk that is independent of ApoB. Mendelian randomization analyses posit a causal relationship. These findings suggest that Lp(a) may be a therapeutic target for AAA and drive the inclusion of AAA as an outcome in clinical trials of Lp(a) antagonists.