Impact of cell type specific variations and age in aortic distensibility

Abstract

Aortic distensibility refers to the ability of arteries to expand in response to pulse pressure generated by the cardiac cycle, and this often decreases with age. Genome-wide association studies have identified genetic variants associated with distensibility; however, the mechanisms leading to changes in distensibility remain unclear. In this study we examined aortic distensibility through the lens of genomics, considering both cellular composition and cell type specific gene expression, inferred from bulk gene expression data, to investigate how these factors contribute to the observed changes in distensibility associated with age and genotype. We found age-related decreases in the proportions of Pericytes and Fibroblast I cells, while the proportion of vascular smooth muscle cells type II (VSMC II) increased. Notably, most of the gene expression changes associated with age were identified in VSMC I, VSMC II and Fibroblast I cells. Furthermore, we observed that the cell type-specific expression of most genes associated with distensibility correlated with age, specifically VSMC I, VSMC II, Fibroblast I, and Pericyte cells. We also tested for genetic associations with the extent of increased distensibility with age in the UK Biobank and found two independent loci, both of which showed a marginally significant association with the increased distensibility with age. None of the identified GWAS SNPs were significantly associated with the inferred cellular proportions. Interestingly, we found two independent SNPs that had a genome-wide significant association with distensibility were also associated with cell type specific expression of nearby genes (SRR in VSMC I, VSMC II and Fibroblast I, as well as CDH13 in VSMC I) that have been implicated in aortic distensibility. Overall, our results identify cell type specific changes in gene expression that may help to explain genetic and age-related variation in this important physiological phenotype.