Differential expression analyses on human aortic tissue reveal novel genes and pathways associated with abdominal aortic aneurysm onset and progression

Abstract

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, sug-gesting 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.

This work was supported by a grant from the Spanish Ministry of Science and Innovation (PID2019-109844RB-I00). The genotyping service was carried out at the Genotyping Unit-CEGEN in the Spanish National Cancer Research Centre, supported by Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. CEGEN is part of the initiative IMPaCT-GENóMICA (IMP/00009) cofunded by the Instituto de Salud Carlos III and the European Regional Development Fund. G. Tempran-Sagrera is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). Dr Sabater-Lleal is supported by a Miguel Servet contract from the Instituto de Salud Carlos III Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. Dr Davtian was funded by a Tenovus Scotland Research PhD studentship, T19-06.