Using genetics to discover mechanisms of abdominal aortic aneurysm

PROJECT SUMMARY/ABSTRACT The goal of this R01 proposal is to advance our understanding of the genetic regulatory mechanisms underlying the newly identified loci associated with abdominal aortic aneurysms (AAA), with the ultimate goal of enabling earlier prevention and treatment of the disease. Our research team comprises individuals from multiple areas of medical research, including high-throughput genetics, computational and statistical genetics, and cardiovascular disease biology. Building upon our past research endeavors centered on coronary artery disease and myocardial infarction, our focus is now to uncover the biological mechanisms that underscore genetic loci linked to AAA, employing a combination of genetics, bioinformatics, as well as cell culture and animal models. During the previous funding period, we have played a crucial role in the Million Hearts Initiative, Global Biobank Meta-analysis Initiative (GBMI), Abdominal Aortic Aneurysm Genetics (AAAGen) Consortium, and a substantial collaboration studying the genetics of atrial fibrillation. In this application, we have outlined two specific aims: In Aim 1, we propose to combine the meta-analysis efforts from AAAGen and GBMI to increase the sample size for candidate gene discovery related to AAA. We will fine-map the associated loci to novel causal genes using bioinformatic tools, together with multi-omics data from abdominal aorta tissue, to prioritize genes for biological follow-up studies. In Aim 2, we plan to define the functions of TCF7L2 within vascular smooth muscle cells, and additionally, elucidate the functional roles of 2 to 5 newly identified candidate genes from Aim 1, in the development of AAA. The accomplishment of these aims will provide invaluable insights into the biological mechanisms underlying AAA and will reveal novel gene targets that hold promise for the better diagnosis, prevention, and treatment of AAA.