System Genetics Analysis Reveals Sex Differences in Human Aortic Smooth Muscle Gene Expression

Background: Coronary artery disease (CAD) is one of the leading causes of death worldwide. The buildup of atherosclerotic plaque, including lipids and cellular waste, characterizes this disease. Smooth muscle cells (SMCs) can migrate and proliferate to form a fibrous cap that stabilizes the atherosclerotic plaque in response to plaque buildup. However, in some severe cases, the fibrous cap is unable to prevent plaque rupture, which can lead to a thrombotic event causing a stroke or myocardial infarction. Studies have been conducted to identify genes associated with this disease. However, the influence of sex on CAD risk is poorly understood due to the complexity of the disease and the lack of women in clinical studies. Methods: This study is investigated with a unique collection of human aortic smooth muscle cells (huASMCs) derived from 118 male and 33 female individuals who either underwent a heart transplant or were victims of motor vehicle accidents. In this investigation, we explore differentially expressed genes between males and females related to atherosclerosis using a unique RNAseq dataset of human aortic SMCs. Results: Our study identified 8 genes (CHST1, DKK2, DLL4, EIF1AXP1, GALNT13, NOTCH4, SELL, SPARCL1) that exhibit sex-biased effects in SMCs. Of these, 6 genes were found in the Athero-Express dataset and 5 of them were associated with atherosclerosis-relevant phenotypes. We discovered a novel NOTCH4/DLL4 pathway that plays a role in the differential expression of these genes between males and females. This pathway is linked to coronary artery physiology and may play a role in the pathophysiology of coronary artery disease that differs between the sexes. Conclusions: Overall, this investigation shows that differentially expressed genes between males and females in human aortic SMCs exist.