AIMS
We assessed the age-specific associations between moderate-to-vigorous physical activity (MVPA) and incident type 2 diabetes.
MATERIALS AND METHODS
We included UK Biobank participants with valid accelerometry data without diabetes mellitus at baseline (N = 87 975; 62.7 years [IQR, 55.6-67.9]; 57% women). We examined whether age, sex and baseline metabolic disease status modified the associations of MVPA volume (lower versus higher) and, in exploratory analyses, MVPA timing (later-day versus earlier-day) with incident type 2 diabetes. Age-specific relative and absolute associations were assessed across 5-year age bins using hazard ratios (HRs) and incidence rate differences (IRDs), and additionally stratified by sex and baseline metabolic disease status.
RESULTS
Associations of MVPA volume with type 2 diabetes were most consistently modified by age, baseline prediabetes (all p-values for interaction < 0.05), with stronger associations observed among participants younger than the median population age (< 62.7 years, HR = 2.44 [95% CI: 2.05-2.90] versus HR = 1.65 [95% CI: 1.47-1.86]) and participants without prediabetes. Across 5-year age groups, HRs declined with age, whereas IRDs increased in the overall population. No clear effect modification was observed for the association between MVPA timing and type 2 diabetes risk.
CONCLUSIONS
The relative association between higher MVPA volume and lower type 2 diabetes risk attenuated with age and was weaker among individuals with prediabetes, whereas absolute risk reductions were larger among older and metabolically higher-risk individuals. These findings support considering both relative and absolute measures when targeting MVPA interventions for type 2 diabetes prevention.
Qiu-Yu Feng, R. Noordam, Deng-Hui Hu et al.· Diabetes, obesity and metabo...· 0 citations
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.
V. Sier, K. Dimitrova, E. Peters et al.· Cardiovascular Research· 0 citations
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