Sex-based differences in myocardial gene expression in recently deceased organ donors with no prior cardiovascular disease

Abstract

Sex differences in the development of the normal heart and the prevalence of cardiomyopathies have been reported. The molecular basis of these differences remains unclear. Sex differences in the human heart might be related to patterns of gene expression. Recent studies have shown that sex specific differences in gene expression in tissues including the brain, kidney, skeletal muscle, and liver. Similar data is limited for the heart. Herein we address this issue by analyzing donor and post-mortem adult human heart samples originating from 46 control individuals to study whole-genome gene expression in the human left ventricle. Using data from the genotype tissue expression (GTEx) project, we compared the transcriptome expression profiles of male and female hearts. We found that genes located on sex chromosomes were the most abundant ones among the sexually dimorphic genes. The majority of differentially expressed autosomal genes were those involved in the regulation of inflammation, which has been found to be an important contributor to left ventricular remodeling. Specifically, genes on autosomal chromosomes encoding chemokines with inflammatory functions (e.g. CCL4, CX3CL1, TNFAIP3) and a gene that regulates adhesion of immune cells to the endothelium (e.g., VCAM1) were identified with sex-specific expression levels. This study underlines the relevance of sex as an important modifier of cardiac gene expression. These results have important implications in the understanding of the differences in the physiology of the male and female heart transcriptome and how they may lead to different sex specific difference in human cardiac health and its control.

Stress Coping Strategies in the Heart: An Integrated View

“…Yet little is known about the precise mechanisms that underlie sex differences and how these impact on prognosis, morbidity or therapeutic choices. There is evidence showing that male and female cardiac cells have distinct gene expression programs ( 182 ), and therefore differ in metabolic capacity. Fortunately, there is now a movement to include both sexes, not only in in vivo studies but also in in vitro studies, as well as to analyze their responses separately.…”

Sexual differences in genetic architecture in UK Biobank

“…In recent years, there has been growing evidence of common genetic variation having different effects on males and females 1,2 . This, along with sex-biases observed in the human transcriptome [3][4][5][6][7][8][9][10] , the presence of a distinct hormone milieu in each sex, and differential environmental pressures arising from gender societal roles 1,11 , has led to an increased study of the potential importance of GxS interactions to understand the underlying biology of complex traits, including the estimation of disease risk. Previous studies have investigated differences in heritability between the sexes (h 2 ) [12][13][14] , departure of genetic correlations from 1 (rg) 12,[14][15][16][17][18] , and performed sex-stratified genome-wide association studies (GWAS) to directly assess differences in the effects of genetic variants between the sexes 6,[19][20][21][22][23][24][25][26] .…”

Noncanonical WNT Activation in Human Right Ventricular Heart Failure

“…The NF group was similarly well-matched across all four cardiomyopathy hemodynamic groups with respect to age, ethnicity, body surface area, and weight, although not for gender ( Supplementary Table 3 ). Previous unbiased studies of cardiac DGE have demonstrated few gender-specific differences, and none in WNT-related gene expression, suggesting a low likelihood that gender differences would impact our findings ( 42 ).…”