"Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk would significantly increase the yield of current screening protocols," Dr. Philip S. Tsao of VA Palo Alto Health Care System, in California, told Reuters Health by email. "In addition, our findings may have implications for future genetically guided therapies to manage progression of AAA."
Previous studies have indicated that the heritability of AAA is as high as 70%, but GWASs have identified only 10 loci that are significantly associated with AAA heritability, Dr. Tsao and colleagues note in Circulation.
For their study, the team used DNA samples and phenotypic data from 7,642 cases and more than 172,000 controls in the Million Veteran Program (MVP). They identified 14 novel genetic loci that were associated with AAA, bringing the total number of known significant AAA loci to 24.
Thirteen of the loci were associated with atherosclerosis in at least one arterial territory, and several DNA sequence variants were associated with a range of known risk factors for AAA, including hyperlipidemia and hypertriglyceridemia.
A genetically increased risk of ever being a regular smoker and a genetic increase in smoking heaviness were both significantly associated with an increased risk of AAA, whereas a genetic increase in the likelihood of smoking cessation was found to protect against AAA.
Genetic variants associated with a rise in diastolic blood pressure were also associated with a significantly increased risk of AAA, whereas there was no significant link between a genetic increase in systolic blood pressure and AAA risk.
"This may have implications from a disease-management standpoint and needs to be studied further," Dr. Tsao said.
Overall, four AAA risk variants demonstrated at least nominal association with cerebral aneurysms, seven were associated with lower extremity aneurysms, and 18 were associated with iliac aneurysms.
A polygenic risk score comprising 29 genetic variants was significantly associated with AAA in the Mayo Clinic Vascular Disease Biorepository and in three additional population-based data sets. In the Mayo Clinic cohort, consisting mostly of people of European ancestry, each one-standard-deviation increase in the score was associated with a 26% increased risk of AAA.
Dr. Declan Bradley of Queens University Belfast, in the U.K., who has participated in several studies examining genetic risk factors for AAA and other aneurysms, told Reuters Health by email, "Despite being a relatively common, serious disease, the causes of abdominal aortic aneurysm are less studied and less understood than many other cardiovascular diseases, so this large study focusing on AAA is very welcome."
"We should always be careful about optimism that genetic risk scores will be used in population screening programs, as their effectiveness needs to be tested in the real-world settings, with more diverse populations," he said. "This study did not aim to evaluate the effectiveness of the genetic risk score as part of a screening program."
Dr. Bradley added, "The study improves our understanding of genetic factors that contribute to the risk of AAA, but it also points strongly to the important role of smoking and raised diastolic blood pressure in AAA development, using the Mendelian randomization method to reduce confounding. This is a reminder that smoking cessation, a healthy diet, and physical activity are the most important messages for primary prevention of AAA."
By Will Boggs MD
SOURCE: https://bit.ly/376tZk4 Circulation, online September 28, 2020.
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