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.

Background: Abdominal aortic aneurysms (AAAs) are focal dilatations of the abdominal aorta that expand progressively, increasing their risk of rupture. Rupture of an AAA is associated with high mortality rates, but the mechanisms underlying the initiation, expansion, and rupture of AAAs are not yet fully understood. We aimed to characterize the pathophysiology of AAAs and identify new genes associated with AAA initiation and progression. Methods and Results: This study used RNA sequencing data on 140 samples, becoming the largest RNA sequencing data set for differential expression studies of AAAs. We performed differential expression analyses and analyses of differential splicing between dilated and nondilated aortic tissue samples, and between AAAs of different diameters. We identified 3002 differentially expressed genes between AAAs and controls that were independent of ischemic time, 1425 of which were new. Additionally, 8 genes ( EXTL3 , ZFR , DUSP8 , DISP1 , USP33 , VPS37C , ZNF784 , RFX1 ) were differentially expressed between AAAs of varying diameters and between AAAs and control samples. Finally, 7 genes ( SPP1 , FHL1 , GNAS , MORF4L2 , HMGN1 , ARL1 , RNASE4 ) with differential splicing patterns were also differentially expressed genes between AAAs and controls, suggesting that splicing differences in these genes may contribute to the observed expression changes and disease development. Conclusions: This study identifies new genes and splicing patterns associated with AAAs and validates previous relevant pathways on AAAs. These findings contribute to the understanding of the complex mechanisms underlying AAAs and may provide potential targets to limit AAA progression and mortality risk.

A variety of disorders are known to be related with aortic geometry, among them abdominal aortic aneurysm (AAA). This work aims to present the main determinants of abdominal aortic diameter in a new cohort of families at high risk of AAA. The Triple-A Genomic Analysis (TAGA) study comprises 407 individuals related in 12 families. Each family was collected through a proband with AAA. We calculated heritability and genetic correlations between abdominal aortic diameter and clinical parameters. A genome-wide linkage scan was performed based on 4.6 million variants. A predictive model was calculated with conditional forest. Heritability of the abdominal aortic diameter was 34%. Old age, male sex, higher height, weight, creatinine levels in serum, and better lung capacity were the best predictors of aortic diameter. Linkage analyses suggested the implication of Epidermal Growth Factor Receptor (EGFR) and Betacellulin (BTC) genes with aortic diameter. This is the first study to evaluate genetic components of variation of the aortic diameter in a population of AAA high-risk individuals. These results reveal EGFR, a gene that had been previously implicated in AAA, as a determinant of aortic diameter variation in healthy genetically enriched individuals, and might indicate that a common genetic background could determine the diameter of the aorta and future risk of AAA.

Objective: The risk of Abdominal Aortic Aneurysm (AAA) rupture is associated with the aneurysm size and growth rate. This study aims to provide a global description of growth rates per intervals of AAA diameter size for individuals in the Spanish population, to understand possible comorbidities associated with growth rate variability, and to assess practitioners on safe follow-up visits for AAA patients. Methods: We present the Triple-A Barcelona Study (TABS), a new hospital-based longitudinal study recruiting consecutive individuals with AAAs in Barcelona. So far, 469 individuals with measurements of the abdominal aortic diameter, along with anthropometric, clinical information, and blood samples for most follow-up visits, have been recruited. Statistical modeling was performed to identify the most relevant predictors of the diameter size and expansion in individuals with AAAs using linear mixed-effect models. Results: The average growth rate per interval was 0.78 (2.34) mm/year for aneurysms with an initial diameter between 30 and 40 mm, 1.22 (3.34) mm/year for aneurysms with an initial diameter between 40 and 50 mm, and 4.12 (5.09) mm/year for aneurysms with an initial diameter equal to or greater than 50 mm. The main factors determining the growth rate beyond the aortic diameter are sex and related comorbidities (COPD and DM). The estimated time to reach the surgical threshold for individuals with small aneurysms exceeded 10 years, on average. Conclusions: Overall, this study serves as a promising step towards the development of better prediction tools to assess clinical decisions in AAA patients in the Spanish population and to guide future screening policies.

Background: Abdominal aortic aneurysms (AAA) are focal dilatations of the abdominal aorta. They are normally asymptomatic and progressively expand, increasing their risk of rupture. Rupture of an AAA is associated with high mortality rates, but the mechanisms underlying the initiation, expansion and rupture of AAA are not yet fully understood. This study aims to characterize and identify new genes associated with the pathophysiology of AAA through differential expression analyses between dilated and non-dilated aortic tissue samples, and between AAA of different diameters. Our study used RNA-seq data on 140 samples, becoming the largest RNA-seq dataset for differential expression studies of AAA. Results: We identified 7,454 differentially expressed genes (DEGs) between AAA and controls, 2,851 of which were new compared to previous microarray studies. Notably, a novel cluster on adenosine triphosphate synthesis regulation emerged as strongly associated with AAA. Additionally, exploring AAA of different diameters identified eight genes ( EXTL3 , ZFR , DUSP8 , DISP1 , USP33 , VPS37C , ZNF784 , RFX1 ) that overlapped with the DEGs between AAA and controls, implying roles in both disease onset and progression. Seven genes ( SPP1 , FHL1 , GNAS , MORF4L2 , HMGN1 , ARL1 , RNASE4 ) with differential splicing patterns were also DEGs between AAA and controls, suggesting that splicing differences contribute to the observed expression changes and the disease development. Conclusions: This study identified new genes and pathways associated with AAA onset and progression and validated previous relevant roles of inflammation and intracellular calcium regulation. These findings provide insights into the complex mechanisms underlying AAA and indicate potential targets to limit AAA progression and mortality risk.