SRS219 - 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. GWA studies have identified genetic variations associated with distensibility; however, the mechanisms behind the changes in distensibility remain unclear. In this study, we examined aortic distensibility through the lens of genomics, considering both cellular composition, inferred from bulk gene-expression data, as well as gene-expression within constituent cell types. This uncovered the factors contributing 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 VSMC-II increased. Notably, most of the age-related gene expression changes 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 in the UK-Biobank for genetic associations with the rate of change of distensibility with age and found two independent loci, both of which showed a marginally significant association with the rate of change of distensibility with age. Interestingly, in our analysis of cell type-specific gene expression, we found specific GWAS SNPs involved in the altered expression of the SRR gene in VSMC-I, VSMC-II, and Fibroblast-I cells, as well as the CDH13 gene in VSMC-II cells. This suggests age-related changes, and the altered expression of genes within these essential cell types may impact genetic variations in this important physiological phenotype.