Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets

Robin J G Hartman,Hester M Den Ruijter,Daniek M C Kapteijn,Michal Mokry,Mete Civelek,Gerard Pasterkamp,Mireille N Bekker,Saskia Haitjema

doi:10.1038/s41598-020-69451-8

Robin J G Hartman, Hester M Den Ruijter + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-69451-8

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Abstract

Sex differences in endothelial cell (EC) biology may reflect intrinsic differences driven by chromosomes or sex steroid exposure and gender differences accumulated over life. We analysed EC gene expression data from boy–girl twins at birth and in non-twin adults to detect sex differences at different stages of life, and show that 14–25% of the EC transcriptome is sex-biased. By combining data from both stages of life, we identified sex differences that are present at birth and maintained throughout life, and those that are acquired over life. Promisingly, we found that genes that present with an acquired sex difference in ECs are more likely to be targets of sex steroids. Annotating both gene sets with data from multiple genome-wide association studies (GWAS) revealed that genes with an intrinsic sex difference in ECs are enriched for coronary artery disease GWAS hits. This study underscores the need for treating sex as a biological variable.

Highlights

Sex differences in endothelial cell (EC) biology may reflect intrinsic differences driven by chromosomes or sex steroid exposure and gender differences accumulated over life
We hypothesized that the sex chromosomes are mainly involved in intrinsic sex differences, i.e. consistently different across the lifespan, while sex steroids and gender differences are the main players for acquired sex differences in human ECs
As it has been shown that genes that present with sex differences in expression are more likely to be less evolutionary conserved in their gene bodies, while their promoter, and their regulation, is more likely to be evolutionary c onserved[8,9,10], we looked at their evolutionary conservation to see whether this is different for acquired and intrinsic sex differences

Summary

Introduction

Sex differences in endothelial cell (EC) biology may reflect intrinsic differences driven by chromosomes or sex steroid exposure and gender differences accumulated over life. We found that genes that present with an acquired sex difference in ECs are more likely to be targets of sex steroids. Annotating both gene sets with data from multiple genome-wide association studies (GWAS) revealed that genes with an intrinsic sex difference in ECs are enriched for coronary artery disease GWAS hits. Differences between female and male cells might be present from birth onwards, or acquired later in life because of sex steroid exposure and gender differences. Transcriptomic studies of female and male (endothelial) cells shed light on differentially expressed genes (DEGs) between the sexes and their regulators, but few have been performed far on ECs4. We determined whether or not the genes with sex differences in EC had associations with (disease) traits in the genome-wide association study (GWAS) catalog

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