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Aortic Aneurysm Risk Affected by Genetic Variants Linked to Artery Diameter 

NEW YORK — Researchers have identified a number of genetic variants that are associated with increased ascending aortic diameter, a risk factor for aortic aneurysm, and have developed a polygenic risk score for the condition. 

Aortic aneurysms and aortic dissections led to nearly 10,000 deaths in the US in 2019, according to the Centers for Disease Control and Prevention. While smoking and hypertension are risk factors for thoracic aortic disease, previous studies have also suggested a genetic influence on those conditions. Diameter of the aortic root — the section of the ascending aorta closest to the heart — is another risk factor, and common genetic variation has previously been linked to this phenotype in European populations. 

To study the genetics further, researchers from Stanford University School of Medicine conducted a genome-wide association study using UK Biobank data to identify 56 genetic loci associated with ascending aorta diameter, including some implicating genes with roles in cardiovascular development. A polygenic risk score based on variants in those loci could further predict risk of thoracic aortic aneurysm in populations of varying ancestral backgrounds. The researchers additionally found through Mendelian randomization analysis that blood pressure has a causal role in aortic dilation. 

"Overall, our findings translate the genetic determinants of normal variation in the size of the aorta both forward and backward, simultaneously identifying determinants of early cardiovascular development while also providing a new approach to thoracic aortic disease," senior author James Priest from Stanford and his colleagues wrote in their paper, which appeared Monday in Nature Genetics.

For their GWAS, the researchers determined ascending aorta diameter from MRI images obtained by the UK Biobank for more than 32,000 individuals of European ancestry. After adjusting for body surface area, they then uncovered 131 genetic variants at 38 different genetic loci associated with ascending aorta diameter. 

The strongest signal could be traced to near the elastin gene, which encodes a protein that is an important part of the aortic wall, giving it and other tissues their elasticity. Loss of heterozygosity in the elastin gene has been tied to Williams syndrome, which is marked by supraventricular aortic stenosis, while duplication of the elastin locus has been linked to aortic dilation. 

Exploratory GWAS uncovered 13 additional loci in participants of African-Afro-Caribbean ancestry and two loci in participants of South Asian ancestry, while a cross-ancestry meta-analysis identified a further three loci, for a total 56 loci linked to ascending aorta diameter. 

The researchers further developed a polygenic risk score for ascending aorta diameter using a training set of more than 20,000 individuals of European ancestry and validated it in a separate set of 12,311 UK Biobank participants. The resulting score encompassed nearly 93,000 variants, and a 1.4-standard deviation increase in that risk score was associated with a 0.64 mm increase in ascending aorta diameter. Further, an increased polygenic risk score for ascending aorta diameter was associated with an increased risk of thoracic aortic aneurysm and of surgical intervention, the researchers found. 

This link held across populations. The researchers reported that an increased polygenic risk score for ascending aorta diameter was also associated with increased risk of thoracic aortic aneurysm in individuals of European ancestry from FinnBank, the Million Veteran Program, and the Penn Medicine Biobank, as well as in individuals of Hispanic ancestry from MVP and African American individuals from MVP and Penn Biobank. Despite this, the researchers added, there is a need to generate population-specific risk scores for ascending aorta diameter. 

A phenome-wide association study further found that increased height, weight, and body fat were linked to a higher polygenic risk score, and an increase in polygenic risk score was associated with raised risk of hypertension. Lipid biomarker levels, meanwhile, were associated with a decreased polygenic risk score. 

Additional Mendelian randomization analysis found that a genetically determined 10 mmHg increase in blood pressure was causal for a 1 mm increase in ascending aorta diameter, suggesting that managing blood pressure could reduce aortic dilation and risk of disease progression. 

"Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta," the researchers wrote.