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Sex differences in gene expression in response to ischemia in the human myocardium

By Gregory Stone, Ashley Choi, Meritxell Oliva, Joshua Gorham, Mahyar Heydarpour, Christine E. Seidman, Jon G. Seidman, Sary F. Aranki, Simon C. Body, Vincent J. Carey, Benjamin A Raby, Barbara E. Stranger, Jochen D. Muehlschlegel

Posted 31 Mar 2018
bioRxiv DOI: 10.1101/282350 (published DOI: 10.1093/hmg/ddz014)

Background: Sex differences exist in the prevalence, presentation, and outcomes of ischemic heart disease. Females have a higher risk of heart failure post-myocardial infarction relative to males and the female sex is an independent risk factor for hospital and operative mortality after cardiac surgery. However, the mechanisms underlying this sexual dimorphism remain unclear. We examined sex differences in human myocardial gene expression in response to ischemia. Methods: Left ventricular biopsies from 68 male and 46 female patients undergoing aortic valve replacement surgery were obtained at baseline and after a median 74 minutes of cold cardioplegic arrest/ischemia and respective transcriptomes were quantified by RNA-Seq. Sex-specific responses to ischemia were quantified by differential gene expression, expression quantitative trait loci (eQTL) and pathway and functional analysis. Cell-type enrichment analysis. was used to obtain an estimate of the identity and relative proportions of different cell types present in each sample. Results: A sex-specific response to ischemia was observed for 271 genes. Functional annotation analysis revealed sex-specific modulation of the oxytocin signaling pathway and common pathway of fibrin clot formation. The eQTL analysis identified variant-by-sex interaction eQTLs at baseline and post-ischemia, indicative of sex differences in the genotypic effects on gene expression, and cell-type enrichment analysis showed sex-bias in the proportion of specific cell types. Conclusion: In response to myocardial ischemia, the human left ventricle demonstrates changes in gene expression that differ between the sexes. These differences provide insight into the sexual dimorphism of ischemic heart disease and may aid in the development of sex-specific therapies that reduce myocardial injury.

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