Sex-specific gene expression signatures of calcific aortic valve stenosis in a large collection of human tissues

Background and Aims:The mechanisms underlying sex differences in calcific aortic valve stenosis (CAVS) are poorly understood.We aimed to uncover sex-specific gene expression signatures of CAVS, including genes located on sexual chromosomes. Methods:We performed mRNA sequencing from the explanted aortic valves of 500 individuals from our institute who underwent aortic valve replacement (n=440) or a heart transplant (n=60).Differential gene expression analyses were performed according to biological sex (n = 175 women; n = 311 men), comparing individuals with severe forms of CAVS to those with no significant CAVS.Interaction analyses were used to identify genes exhibiting sex-specific variations in differential expression magnitude.We prioritized differentially expressed genes (DEGs) known to escape X chromosome inactivation (XCI) and with higher gene expression in women.Results: When comparing valves with severe CAVS to valves with no significant CAVS, we identified 2556 DEGs on the autosomes in female samples, and 2042 DEGs in male samples (|FC|2, FDR<5%).The interaction analysis revealed 114 genes with significantly different changes between sexes (FDR<5%).We prioritized 39 genes specifically dysregulated in women, primarily involved in extracellular matrix organization and cell adhesion, such as PRSS2 and MMP12.In contrast, 24 genes were more strongly dysregulated in men, including a mineralization network involving DMP1 and MEPE.Genes known to escape XCI, like PRKX and GYG2, showed evidence of sex-specific dysregulation.