Sex differences in the genetic and molecular mechanisms of coronary artery disease

• Published in: Atherosclerosis 2023-11, Vol.384, p.117279-117279, Article 117279
• Main Authors: Sakkers, Tim R., Mokry, Michal, Civelek, Mete, Erdmann, Jeanette, Pasterkamp, Gerard, Diez Benavente, Ernest, den Ruijter, Hester M.
• Format: Article
• Language: English
• Subjects: Atherosclerosis; CAD; Epigenetics; Genetics; Sex differences; Transcriptomics
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2023.117279

Sex differences in coronary artery disease (CAD) presentation, risk factors and prognosis have been widely studied. Similarly, studies on atherosclerosis have shown prominent sex differences in plaque biology. Our understanding of the underlying genetic and molecular mechanisms that drive these differences remains fragmented and largely understudied. Through reviewing genetic and epigenetic studies, we identified more than 40 sex-differential candidate genes (13 within known CAD loci) that may explain, at least in part, sex differences in vascular remodeling, lipid metabolism and endothelial dysfunction. Studies with transcriptomic and single-cell RNA sequencing data from atherosclerotic plaques highlight potential sex differences in smooth muscle cell and endothelial cell biology. Especially, phenotypic switching of smooth muscle cells seems to play a crucial role in female atherosclerosis. This matches the known sex differences in atherosclerotic phenotypes, with men being more prone to lipid-rich plaques, while women are more likely to develop fibrous plaques with endothelial dysfunction. To unravel the complex mechanisms that drive sex differences in CAD, increased statistical power and adjustments to study designs and analysis strategies are required. This entails increasing inclusion rates of women, performing well-defined sex-stratified analyses and the integration of multi-omics data. [Display omitted] •The genetic and molecular mechanisms that drive sex differences in coronary artery disease remain largely understudied.•Reviewing (epi)genetic studies suggests sex differences in vascular remodeling, lipid metabolism and endothelial function.•Transcriptomic studies suggest that phenotypic switching of smooth muscle cells contributes to atherosclerosis in women.•Future research would require higher inclusion rates of women and well-defined sex-stratified multi-omics analyses.