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Polygenic Risk Score Identifies Patients at Increased Risk for Abdominal Aortic Aneurysm and May Benefit from Ultrasound Screening

      Background

      Abdominal aortic aneurysm (AAA) is a significant heritable cause of cardiovascular related mortality, yet published genome-wide association studies have only identified 10 genome-wide significant (P < 5 × 10–8) risk loci to date. In addition, current AAA screening recommendations remain limited to men age 65 to 75 with a history of smoking. Genetic variants affecting multiple biological pathways are associated with AAA risk and may help to identify asymptomatic individuals at higher risk for disease.

      Methods

      Using electronic health record data, we identified individuals with and without clinical AAA in Million Veteran Program (MVP) participants. Individuals were genotyped on a customized Affymetrix array, and we tested 18 million genotyped and imputed DNA variants for association with AAA using logistic regression models adjusting for age, sex and population structure. We then performed replication in external datasets and set a P < 5 × 10–8 for statistical significance. In downstream analyses, we tested and validated a series of AAA polygenic risk scores (PRS) and assessed the associated AAA risk per standard deviation increase in PRS using prevalent data from an independent set of MVP participants (1656 AAA cases; 44,908 controls). We set a P value of less than .05 for statistical significance.

      Results

      We identified 7642 AAA cases and 172,172 controls. Following replication, we identified 14 novel AAA loci implicating known risk factors including lipids (LPA, PCSK9) and smoking (CHRNA3). We generated a 29 variant PRS and observed that a 1 standard deviation increase in the AAA PRS was associated with a 32% increased risk of AAA (odds ratio, 1.32; PPRS = 1.7 × 10–34). Men in MVP with the 5% highest PRS and over 50 years of age had a disease prevalence of 7.8% (142/1680), higher than that observed in AAA screening trials informing current guidelines.

      Conclusions

      Here, we identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased risk of AAA. Our data suggest that extending current screening guidelines to include testing for those with high polygenic AAA risk would significantly increase the yield of current screening.