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

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.

SUBMITTER: Hartman RJG

PROVIDER: S-EPMC7378217 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Hartman Robin J G RJG Kapteijn Daniek M C DMC Haitjema Saskia S Bekker Mireille N MN Mokry Michal M Pasterkamp Gerard G Civelek Mete M den Ruijter Hester M HM

Scientific reports 20200723 1

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 through ...[more]

PMID: 32704153

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Project description:The importance of gonadal hormones in the regulation of vascular function has been documented. An alternate and essential contribution of the sex chromosomes to sex differences in vascular function is poorly understood. We reported previously sex differences in microvessel permeability (P(s)) responses to adenosine that were mediated by the cAMP signaling pathway (Wang J, PhD thesis, 2005; Wang J and Huxley V, Proceedings of the VIII World Congress of Microcirculation, 2007; Wang J and Huxley VH, Am J Physiol Heart Circ Physiol 291: H3094-H3105, 2006). The two cyclic nucleotides, cAMP and cGMP, central to the regulation of vascular barrier integrity, are hydrolyzed by phosphodiesterases (PDE). We hypothesized that microvascular endothelial cells (EC) would retain intrinsic and inheritable sexually dimorphic genes with respect to the PDEs modulating EC barrier function. Primary cultured microvascular EC from skeletal muscles isolated from male and female rats, respectively, were used. SRY (a sex-determining region Y gene) mRNA expression was observed exclusively in male, not female, cells. The predominant isoform among PDE1-5, present in both XY and XX EC, was PDE4. Expression mRNA levels of PDE1A (male > female) and PDE3B (male < female) were sex dependent; PDE2A, PDE4D, and PDE5A were sex independent. Barrier function, P(s), was determined from measures of albumin flux across confluent primary cultured microvessel XY and XX EC monolayers. Consistent with intact in situ microvessels, basal monolayer P(s) did not differ between XY (1.7 +/- 0.2 x 10(-6) cm/s; n = 8) and XX (1.8 +/- 0.1 x 10(-6) cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) P(s) in XX, not XY, cells. These findings demonstrate the presence and maintenance of intrinsic sex-related differences in gene expression and cellular phenotype by microvascular EC in a gonadal-hormone-free environment. Furthermore, intrinsic cell-sex likely contributes significantly to sexual dimorphism in cardiovascular function.

Project description:BackgroundCoronary artery bypass grafting (CABG) is associated with both cardiovascular disease (CVD) and non-CVD traits. In addition, women's prognosis after coronary events and revascularizations is worse than in men. As the course of CVD in women differs from that of men, we performed a phenome-wide analysis on the sex differences in CABG -related morbidity and mortality.Materials and methodsWe performed an untargeted analysis on the sex differences in predictors and outcomes of CABG. We studied a sample of 176,680 FinnGen participants, including 5,950 individuals who underwent CABG (4,988 men and 962 women) and were followed between 1998 and 2019. Over 1,100 different traits were analyzed for both sexes and the results were adjusted with age, smoking status and BMI. Cox proportional hazards models with sex-trait interactions were used to estimate the associations between (1) traits and incident CABG; and (2) CABG and incident traits.ResultsIn women, CABG was more strongly related to greater increases in risk of diseases such as hypertension, Alzheimer's, aortic aneurysms, gout, and chronic kidney disease compared to risk increases observed in men (all interaction p-values < 0.03). After CABG, men had 2.5-fold (p = 3.1E-15) and women 6.3-fold (p = 9.4E-08) greater risk of cardiac death compared to same-sex individuals who did not undergo CABG (p for interaction 8.2E-4). Moreover, the risk of death in women remained higher even 12 years after CABG, whereas the long-term risk of death in men was not increased, compared to same-sex individuals who did not undergo CABG.ConclusionThe adverse outcomes after CABG, both quantity and quality, also appear to differ between men and women. In women, CABG is related to greater long-term increases in risk of cardiac death and several other disease states than in men. Consideration should therefore be given to whether women receive adequate long-term post-operative therapy and follow-up as CABG is not associated with equally improved cardiovascular disease prognosis in women than in men.

Project description:ObjectiveControversy exists about the coronary artery disease (CAD) risk conveyed by diabetes in young and middle-aged women. We investigated sex differences in CAD by diabetes status among healthy individuals with different underlying risks of heart disease.Research design and methodsWe examined subjects aged <60 years without CAD at enrollment in the high-risk GeneSTAR Study (n = 1,448; follow-up ∼12 years), Multi-Ethnic Study of Atherosclerosis (MESA; n = 3,072; follow-up ∼7 years), and National Health and Nutrition Examination Survey III (NHANES III) Mortality Follow-up Study (n = 6,997; follow-up ∼15 years). Diabetes was defined by report, hypoglycemic use, and/or fasting glucose ≥126 mg/dL. The outcome was any CAD event during follow-up (fatal CAD in NHANES).ResultsIn the absence of diabetes, CAD rates were lower among women in GeneSTAR, MESA, and NHANES (4.27, 1.66, and 0.40/1,000 person-years, respectively) versus men (11.22, 5.64, and 0.88/1,000 person-years); log-rank P < 0.001 (GeneSTAR/MESA) and P = 0.07 (NHANES). In the presence of diabetes, CAD event rates were similar among women (17.65, 7.34, and 2.37/1,000 person-years) versus men (12.86, 9.71, and 1.83/1,000 person-years); all log-rank P values > 0.05. Adjusting for demographics, diabetes was associated with a significant four- to fivefold higher CAD rate among women in each cohort, without differences in men. In meta-analyses of three cohorts, additionally adjusted for BMI, smoking, hypertension, HDL, and non-HDL cholesterol, antihypertensive and cholesterol-lowering medication use, the hazard ratio of CAD in men versus women among nondiabetes was 2.43 (1.76-3.35) and diabetes was 0.89 (0.43-1.83); P = 0.013 interaction by diabetes status.ConclusionsThough young and middle-aged women are less likely to develop CAD in the absence of diabetes, the presence of diabetes equalizes the risk by sex. Our findings support aggressive CAD prevention strategies in women with diabetes and at similar levels to those that exist in men.

Project description:BackgroundWomen have been underrepresented in the literature; the effects of female sex on outcomes in patients with acute myocardial infarction (AMI) remain unclear.ObjectivesThis study compares the real-world outcomes of women and men with AMI who have undergone revascularization via percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG).MethodsThis is a retrospective cohort study utilizing data from the Taiwan National Health Insurance database. We identified patients who were admitted for AMI and who underwent coronary revascularization during the index admission period between January 1, 2001, and December 31, 2013. Patients were then categorized based on the treatment received into PCI and CABG groups. In-hospital and long-term outcomes were compared between women and men in each group. Interaction tests were then performed to determine whether the differences between sexes were modified by the mode of revascularization. Analyses were repeated after propensity score matching between women and men in each group to minimize possible confounders. We also conducted subgroup analyses, stratifying by the presence of diabetes mellitus, congestive heart failure, and chronic kidney disease.ResultsWe enrolled 67,534 patients who met the inclusion criteria in the analysis; 60,207 patients had undergone PCI (13,514 female and 46,693 male), while 7327 patients had received CABG (1762 female and 5565 male). Prior to matching, enrolled female patients were older on average, with more comorbidities. In-hospital and long-term outcomes were worse in women, particularly in the PCI group. After matching, the incidence of hospitalization for heart failure (HHF) was higher in women (10.4% vs 8.0%, OR 1.32, 95% CI 1.22-1.43), with fewer repeat revascularizations (28.1% vs 32.4%, OR 0.84, 95% CI 0.81-0.88). Both observations were more pronounced in the PCI group (HHF: P for interaction = 0.0496; repeat revascularization: P for interaction = 0.021).ConclusionsWomen presenting with AMI exhibited worse in-hospital and long-term outcomes than men, especially among women who received PCI as the initial mode of revascularization. Women who underwent PCI were more likely to be admitted for heart failure during follow-up. Possible socioeconomic inequalities or a distinct pathobiology of cardiac ischemia between sexes may underlie these results; thus, further investigation is needed.

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

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

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