Linking single nucleotide polymorphisms to signaling blueprints in abdominal aortic aneurysms

Abstract

Abdominal aortic aneurysms (AAA) is a multifactorial complex disease with life-threatening consequences. While Genome-wide association studies (GWAS) have revealed several single nucleotide polymorphisms (SNPs) located in the genome of individuals with AAA, the link between SNPs with the associated pathological signals, the influence of risk factors on their distribution and their combined analysis is not fully understood. We integrated 86 AAA SNPs from GWAS and clinical cohorts from the literature to determine their phenotypical vulnerabilities and association with AAA risk factors. The SNPs were annotated using snpXplorer AnnotateMe tool to identify their chromosomal position, minor allele frequency, CADD (Combined Annotation Dependent Depletion), annotation-based pathogenicity score, variant consequence, and their associated gene. Gene enrichment analysis was performed using Gene Ontology and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to identify network integration with associated genes and functions. 15 SNPs affecting 20 genes with a CADD score above ten were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 SNP obtained high frequency in AAA and associated with proinflammatory and vascular remodeling phenotypes. SNPs presence positively correlated with hypertension, dyslipidemia and smoking history. GO showed that AAA SNPs and their associated genes could regulate lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that part of these AAA traits could stem from genetic abnormalities. We show a library of inborn SNPs and associated genes that manifest in AAA. We uncover their pathological signaling trajectories that likely fuel AAA development.

Comparative Genome-Wide Analysis of Two Caryopteris x Clandonensis Cultivars: Insights on the Biosynthesis of Volatile Terpenoids

“…COG terms are ancestrally conserved regions, GO terminology in contrast proposes functional annotation of each hypothetical gene. A gene-set enrichment analysis was conducted with GO terms as a source for gene sets [ 58 ]. The following figures show the GO term clustering regarding the three main categories in plants: biological process ( Figure 4 ), molecular function ( Figure 5 ) and cellular components ( Figure 6 ).…”

“…The GO analysis was visualized using REVIGO [ 59 ]. Respective cluster position within the semantic space is irrelevant, as similar semantic terms are located in vicinity of each other in the plot [ 58 ].…”

N6-methyladenosine-associated genetic variants in NECTIN2 and HPCAL1 are risk factors for abdominal aortic aneurysm

“… 7 , 8 These AAA-specific SNPs and their associated genes have been found to modulate extracellular matrix organization, inflammation, lipid metabolism, oxidative stress, and smooth muscle cell function, suggesting that part of these AAA pathological traits could stem from genetic abnormalities. 9 Genetic regulation of gene expression has been fully described in many human tissue types, and expression quantitative trait loci (eQTLs) seem to underlie a considerable fraction of variant-trait associations. 10 Mapping of eQTLs has been conducted to associate SNPs with risk genes in vascular cells and tissues.…”