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

Area of Science:

• Cardiovascular Biology
• Genomics
• Atherosclerosis Research

Background:

• Coronary artery disease (CAD) is a major global cause of mortality, characterized by atherosclerotic plaque buildup.
• Smooth muscle cells (SMCs) play a role in plaque stabilization, but rupture can lead to severe thrombotic events.
• The influence of sex on CAD risk remains poorly understood due to disease complexity and underrepresentation of women in studies.

Purpose of the Study:

• To investigate sex-based differences in gene expression within human aortic smooth muscle cells (huASMCs).
• To identify specific genes and pathways involved in sex-biased regulation related to atherosclerosis.
• To explore the potential impact of these differences on coronary artery disease (CAD) pathophysiology.

Main Methods:

• Analysis of a unique RNA sequencing dataset from huASMCs of 118 males and 33 females.
• Comparison of gene expression profiles between male and female individuals.
• Validation of identified genes using the Athero-Express dataset.

Main Results:

• Identified 8 genes (CHST1, DKK2, DLL4, EIF1AXP1, GALNT13, NOTCH4, SELL, SPARCL1) with sex-biased expression in huASMCs.
• Found 6 of these genes in the Athero-Express dataset, with 5 linked to atherosclerosis phenotypes.
• Discovered a novel NOTCH4/DLL4 pathway implicated in differential gene expression between sexes.

Conclusions:

• Significant differences in gene expression exist between male and female huASMCs.
• The identified NOTCH4/DLL4 pathway is linked to coronary artery physiology and may contribute to sex-specific CAD.
• These findings highlight the importance of considering sex in cardiovascular disease research.