Linking single nucleotide polymorphisms to metabolic risk and matrix remodeling in abdominal aortic aneurysms

Abstract

Abstract Introduction: Genetic hereditary predisposes to AAA. However, the pathobiological relevance of single nucleotide polymorphisms (SNPs) to the development of AAA is not fully elucidated. The present study investigated 86 AAA SNPs from GWAS and clinical cohort studies to determine their phenotypical vulnerabilities in AAA. Methods SNPs from GWAS catalog and available clinical cohort were collected in this study. The SNPs were annotated using snpXplorer AnnotateMe tool to identify its chromosomal position, minor allele frequency (MAF), CADD (Combined Annotation Dependent Depletion)-annotation based pathogenicity score, variant consequence, & their affected gene. Gene enrichment analysis was performed on AAA-related genes using Gene Ontology (GO) terms and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to reveal an association network integration of the SNPs with associated genes and functions. Results 15 SNPs affecting 20 genes with a CADD pathogenicity score above 10 were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 KLK1 obtained high frequency in AAA (17.8%) and was associated with proinflammatory and vascular remodeling phenotypes. Our clinical cohort identified significant positive association of the SNPs presence with aortic diameter (P = 2.003e− 05), hypertension (P = 0.013), dyslipidemia (P = 0.042), and smoking history (P = 0.037) in AAA groups. Gene-ontology and Network association analysis showed that AAA SNPs and their associated genes could regulate signaling pathways including lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that these AAA traits could be inheritable. Conclusion We show a library of inborn SNPs and associated genes that manifest in the presence of risk factors and uncovered their pathological signaling traits that are likely transmitted through familial lineage culminating in AAA development.