Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
Roychowdhury T., Klarin D., Levin MG., Spin JM., Rhee YH., Deng A., Headley CA., Tsao NL., Gellatly C., Zuber V., Shen F., Hornsby WE., Laursen IH., Verma SS., Locke AE., Einarsson G., Thorleifsson G., Graham SE., Dikilitas O., Pattee JW., Judy RL., Pauls-Verges F., Nielsen JB., Wolford BN., Brumpton BM., Dilmé J., Peypoch O., Juscafresa LC., Edwards TL., Li D., Banasik K., Brunak S., Jacobsen RL., Garcia-Barrio MT., Zhang J., Rasmussen LM., Lee R., Handa A., Wanhainen A., Mani K., Lindholt JS., Obel LM., Strauss E., Oszkinis G., Nelson CP., Saxby KL., van Herwaarden JA., van der Laan SW., van Setten J., Camacho M., Davis FM., Wasikowski R., Tsoi LC., Gudjonsson JE., Eliason JL., Coleman DM., Henke PK., Ganesh SK., Chen YE., Guan W., Pankow JS., Pankratz N., Pedersen OB., Erikstrup C., Tang W., Hveem K., Gudbjartsson D., Gretarsdottir S., Thorsteinsdottir U., Holm H., Stefansson K., Ferreira MA., Baras A., Kullo IJ., Ritchie MD., Christensen AH., Iversen KK., Eldrup N., Sillesen H., Ostrowski SR., Bundgaard H., Ullum H., Burgess S., Gill D., Gallagher K., Sabater-Lleal M., DiscovEHR None., Regeneron Genetics Center None., UK Aneurysm Growth Study None., DBDS Genomic Consortium None., VA Million Veteran Program None., Surakka I., Jones GT., Bown MJ., Tsao PS., Willer CJ., Damrauer SM.
Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.