Sex-specific effects of depression on the incidence and risk factors for coronary heart disease: insights from multi-omics approaches.

Sex differences in the associations of multidomain risk factor profiles with incident major adverse cardiovascular events

Major adverse cardiovascular events (MACE) exhibit sex-specific disparities, but comprehensive analyses of combined genetic and clinical risk factor profiles across sexes remain limited. This prospective cohort study included 397,806 UK Biobank participants (55.1% female) without baseline MACE. Five weighted risk scores [social-demographic, lifestyle, metabolic, clinical comorbidity, polygenic risk score (PRS)] were evaluated for associations with incident MACE via sex-stratified Cox proportional hazards regression, interaction analyses, and population-attributable risk (PAR) assessments. Over a median follow-up of 15.6 years, 32,019 participants (8.0%) developed MACE (11.1% males vs. 5.5% females). Social-demographic (Interaction effect: HR 0.91, 95% CI 0.89–0.93), lifestyle (Interaction effect: HR 0.94, 95% CI 0.91–0.97), and clinical comorbidity (Interaction effect: HR 0.85, 95% CI 0.82–0.87) scores exhibited stronger MACE associations in females than males, while males had higher PRS-related risk (Interaction effect: HR 1.07, 95% CI 1.03–1.11, P for interaction < 0.001). Pairwise interaction patterns differed by sex. PRS integration improved MACE prediction in males ( Δ C-statistic = 0.010, P  < 0.001) but not in females ( Δ C-statistic = 0.005, P  = 0.299). PAR ranking differed: while social-demographic and clinical comorbidity scores remained the top two contributors across sexes, polygenic risk emerged as the third largest contributor in males (15.9%), and unhealthy lifestyle was the third largest in females (15.6%). Sex-specific differences in the effects and contributions of risk factor profiles highlight the need for tailored MACE prevention strategies. Polygenic risk provided modest additional discrimination in males, supporting further evaluation of precise cardiovascular risk assessment.

Healthcare burden of comorbid depression and type 2 diabetes and conventional risk factors - a population-based mediation analysis of 0.5 million Chinese people.

BACKGROUND Limited population-based analyses of associations of comorbid depression and diabetes have tested metabolic risk factors as mediating variables for the association between depression and clinical outcomes. METHODOLOGY We included Chinese adults with type 2 diabetes attending structured diabetes risk assessment in Hong Kong between 1 January 2000 and 30 June 2024. Depression was identified using International Classification of Disease-9 codes or prescription of anti-depressants. People with baseline cardiovascular disease or end-stage kidney disease (ESKD) were excluded. We estimated the hazard ratio (HR) of cardiovascular diseases, ESKD, all-cause death associated with depression compared to those without depression. We examined the mediating effects of eight cardiometabolic risk factors in these risk associations. RESULTS Among 571,129 people with type 2 diabetes, 7.5% had depression (mean age 60.4 years, 66.1% women, mean HbA1c 7.2%). People with depression had greater number of all-cause hospitalisation and longer length of stay. Compared to no depression, depression was associated with higher hazards for incident cardiovascular disease (HR: 1.21 [1.17, 1.24]), all-cause death (HR: 1.30 [1.26, 1.33]), but not ESKD (HR 0.95 [0.89, 1.01]), adjusted for age, sex and diabetes duration. Mediation analyses revealed the association between depression, cardiovascular disease and all-cause death were mediated predominantly by the direct effect of depression. CONCLUSION Depression is associated with greater risks for incident cardiovascular disease and all-cause death in people with type 2 diabetes. Mediation analyses revealed minor contributions from metabolic risk factors on these associations, highlighting the need for enhanced screening for depression and integrated care.

Application of competing risks models in cardiovascular mortality research: findings from the Tehran lipid and glucose study

Sex-Related Disparities in Cardiometabolic Burden Among a Large Algerian Cohort

Background: Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Historically, male sex was considered a cardiovascular risk factor however recent accumulating data suggest complex interaction between sex and CVD leading to specific inequalities affecting both males and females with specific cardiometabolic features. Methods: Data from a large nationwide screening cohort were used to assess the cardiometabolic burden among males vs females in Algeria. The prevalence and adjusted Odds Ratio (aOR) of major CVD diseases were compared across the study cohorts. Records of systolic (SBP) and diastolic blood pressure (DBP), as well as findings of clinical examination, ECG, and echocardiography were collected and reviewed for analysis. Results: A total of 21,522 patients were included among them 12,015 were females and 9,507 were males. The latter group had higher age (median age: 60 [51.00-68.00] vs 57 [49.00-65.00] years; p< 0.001), sitting DBP (83 [76.00-92.00] vs 80 [75.00-90.00]; p< 0.001), standing SBP (142 [130.00-160.00] vs 140 [124.00-154.00] mmHg; p< 0.001), smoking (22.1% vs 0.9%; p<0.001) and unknown diabetes (15.2% vs 13.2%; p< 0.001) rates. Moreover, females showed an overall worse cardiometabolic profile while males had a greater burden of ischemic heart disease, arrhythmia, conduction abnormalities, and left ventricular dysfunction. On multivariate analysis, female sex was correlated with higher aOR for known hypertension (aOR:1.55; 95%CI:1.40-1.72; p<0.001) and known dyslipidaemia (aOR: 1.23; 95%CI:1.09-1.39; p=0.001). On the other hand, female sex predicted lower risk of any CVD (aOR:0.84; 95%CI:0.72-0.98; p=0.028) and known cardiovascular disease (aOR: 0.79; 95%CI: 0.67-0.94; p=0.007). Conclusion: CVD affect males and females differently which reflects multifaceted biological, cardiometabolic, and sociodemographic disparities. These findings highlight the need to reduce the sex gap in the prevention and management of CVD. Keywords: Cardiovascular disease; Sex; Management disparities; Sex Gap; North Africa; Algeria

Joint Effects of Long-Term Obesity and Genetic Susceptibility on Sex-Specific Brain Aging.

OBJECTIVE This study aimed to examine the associations of longitudinal obesity trajectories and polygenic risk with sex-specific brain aging. METHODS We analyzed 35,092 UK Biobank participants (16,484 males and 18,608 females). Sex-specific XGBoost models estimated multimodal brain age. We derived 16-year longitudinal obesity trajectories from repeatedly collected anthropometric measurements. Polygenic risk scores were constructed based on 55 independent genetic loci. Multivariable logistic regression examined associations of obesity trajectories and genetic risk with brain age acceleration. RESULTS A total of 8198 (49.73%) males and 9089 (48.84%) females had accelerated brain aging. High genetic risk significantly increased brain age acceleration odds (males: OR = 1.39; females: OR = 1.34). Crucially, the high-stable obesity trajectory exerted a stronger effect in males (OR = 1.90, 95% CI: 1.64-2.21) than in females (OR = 1.25, 95% CI: 1.12-1.40), with the joint presence of high genetic risk and high-stable obesity amplifying risk to an OR of 2.78 in males and 1.57 in females. Conversely, shifting from obesity to non-obesity reduced risk by 30% in males and 18% in females. CONCLUSIONS These findings underscore long-term obesity as a critical, sex-dimorphic driver of accelerated brain aging, and midlife weight management offers robust neuroprotection even in genetically susceptible individuals.

Sex-specific associations of the plasma-proteome with incident coronary artery disease.

AIMS The etiology of coronary artery Disease (CAD) appears different for men and women, yet insights into underlying sex-specific biological mechanisms are limited. We integrated genomic and proteomic analyses to investigate sex-specific associations of the plasma-proteome with CAD. METHODS AND RESULTS In 40,829 UK Biobank participants (free-of-CAD, baseline-365 days thereafter; 55% women; mean age 56.9 ± 8.1 years), we examined associations between 2,922 plasma proteins and incident CAD over a median follow-up of 13.7 years (IQR 13.1-14.4) using multivariable-adjusted Cox proportional hazards models. Sex-specific analyses identified 440 female exclusive and 32 male exclusive proteins associated with incident CAD (FDR-corrected p < 0.05), revealing distinct pathway enrichments, including innate immune response in women and angiogenesis in men. Causality was assessed through combined and sex-stratified two-sample Mendelian randomization (MR) using inverse-variance-weighted analyses with genome wide association summary statistics from 422,108 men (61,969 cases) and 521,695 women (27,128 cases) (UK Biobank, FinnGen freeze 9). Integration of direct sex-protein interaction analyses with sex-combined MR identified 59 proteins with evidence for sex-specific causal effects. Four proteins demonstrated concordant directionality in sex-stratified MR analyses (n = 943,803) and multivariable regression models, namely CDKN2D, MYH9, and SKAP2 (women), and CTSH (men). To assess translational relevance, prioritized targets were further evaluated in secondary major adverse cardiovascular events among carotid endarterectomy patients (MACE; Athero-Express) and acute myocardial infarction (AMI; MISSION!) using plasma proteomics and ELISA. After further top-target identification in the context of MACE and AMI, clinical drug candidates were identified through a machine learning framework, including CTSH (men), and TNFRSF4 (both sexes). CONCLUSIONS We identified sex-specific associations of proteins and biological pathways with incident CAD. Whereas the majority of proteins had consistent associations in both men and women, our findings suggest a degree of sex-specific pathogenesis with evidence for potential causality, opening new alleys for tailored prevention strategies and clinical cardiovascular risk management.