BACKGROUND AND AIMS
Atherothrombotic cardiovascular disease (CVD) risk prediction in older adults remains suboptimal. The relative contributions of circulating protein biomarkers and polygenic scores (PGS) are uncertain.
METHODS
In 10,433 older individuals aged ≥70 years without prior CVD events, we evaluated traditional risk factors alongside three circulating biomarkers (high-sensitivity C-reactive protein, hsCRP; N-terminal pro-b-type natriuretic peptide, NT proBNP; and high-sensitivity troponin I, hsTnI), and two PGSs (coronary artery disease, ischemic stroke) for prediction of major adverse cardiovascular events (MACE). Associations were assessed using Cox proportional hazards models. Model performance was evaluated using the C-index, calibration, and continuous net reclassification improvement (NRI).
RESULTS
Over a median follow-up of 4.5 years (interquartile range 3.4-5.5), 359 MACE occurred. Each biomarker and both PGSs were independently associated with MACE, with NT-proBNP showing the strongest association (adjusted HR per SD 1.50, 95% CI 1.36-1.65). Compared with the base clinical model, the addition of the three circulating biomarkers (hsCRP, NT-proBNP, and hsTnI) resulted in a greater improvement in discrimination than the addition of the two PGSs (ΔC-index +0.041 vs. +0.016). The fully combined model achieved the highest discrimination (C-index 0.734) with good calibration. Circulating biomarkers improved reclassification primarily through correct identification of non-cases (NRI 0.34), whereas PGSs contributed relatively more to identification of cases (NRI 0.31).
CONCLUSIONS
In older adults, circulating biomarkers and PGSs provide cumulative information for CVD risk prediction, contributing differently to discrimination and risk reclassification. Integrating biomarkers and genetic risk may improve CVD risk prediction in older people beyond traditional risk factors.
Cheng-Long Yu, C. Tran, J. Neumann et al.· Atherosclerosis· 0 citations
Summary Background Guideline-recommended clinical risk scores such as AusCVDRisk underestimate cardiovascular disease (CVD) risk in a substantial proportion of individuals who later experience events, with up to 65% initially classified as low or intermediate risk. This limitation is most consequential in the intermediate-risk group, where treatment decisions are uncertain and additional risk refinement could alter management. Circulating lipid species and inherited genetic variation capture complementary molecular aspects of atherosclerotic risk that are not fully reflected by conventional clinical variables, but are not routinely incorporated into primary-care risk assessment. We investigated whether selective integration of lipidomic and genomic risk signals into AusCVDRisk improves 5-year CVD prediction and reclassification, with a focus on individuals at intermediate clinical risk. Methods A lipidomic score comprising 689 lipid species measured by liquid chromatography–tandem mass spectrometry was derived using regularised Cox regression in 8082 participants from the Australian Diabetes, Obesity and Lifestyle Study (1999–2000). A genome-wide coronary artery disease polygenic score (PGS002048; 762,124 variants) was optimised in 3328 participants from the Busselton Health Study (1994–95). Each score was adjusted for AusCVDRisk predictors to isolate independent effects and incorporated into Cox models retaining the AusCVDRisk linear predictor as a fixed offset, generating lipidomic-enhanced (L.CVDRisk), genomic-enhanced (G.CVDRisk), and combined (LG.CVDRisk) scores. Internal and external validation was performed across five Australian cohorts totalling 13,521 adults without baseline CVD. Discrimination (Harrell’s concordance index; C-statistic), calibration, categorical net reclassification improvement (NRI), and decision-curve analyses were assessed. Findings LG.CVDRisk showed modest gains in discrimination compared with AusCVDRisk (pooled ΔC among intermediate-risk individuals 0.071, 95% CI 0.033–0.109; overall 0.012, 95% CI 0.000–0.024). Risk classification improved substantially (pooled NRI in the intermediate-risk group 0.305, 95% CI 0.212–0.397; overall 0.080, 95% CI 0.031–0.129), with net event and non-event reclassification of 38.2% (95% CI 29.3–47.0%) and −6.8% (95% CI −9.3 to −4.2%) among intermediate-risk individuals. Decision-curve analysis showed the greatest net benefit when molecular profiling was selectively applied to individuals with intermediate AusCVDRisk (5–<10%). In a coronary imaging cohort, LG.CVDRisk reclassified 17 (41%) of 41 intermediate-risk individuals with extensive coronary calcification into the high-risk category. Interpretation Selective augmentation of an established clinical risk algorithm with lipidomic and genomic information improves cardiovascular risk stratification among individuals at intermediate baseline risk. This approach supports targeted molecular testing within existing primary-care pathways to inform personalised prevention. Funding National Heart Foundation, Australia, Australian Government Medical Research Future Fund, National Health and Medical Research Council, Victorian Government.
Aleksandar Dakic, Jing-Qin Wu, Tingting Wang et al.· EClinicalMedicine· 0 citations
Low‐dose aspirin is no longer routinely recommended for the primary prevention of cardiovascular disease in older adults due to a lack of net benefit over bleeding risk. We hypothesized that genetic subgroups may experience differential harm or benefit from aspirin therapy. To investigate this, we screened 572 polygenic scores (PGSs) for modification of aspirin's effect on major bleeding and major adverse cardiovascular events (MACE) in the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, placebo‐controlled trial of daily 100 mg aspirin. Participants were aged ≥70 years (≥65 years for US minorities) and free of cardiovascular disease, dementia, or physical disability at enrolment. Among participants with high‐quality genotyping data (n = 13,571), PGS–aspirin interactions were tested using Cox proportional hazards models with Bonferroni correction for multiple testing. During a median follow‐up of 4.6 years, 414 major bleeding events and 464 MACE occurred. A triglyceride‐related PGS (PGS003144) significantly modified aspirin‐associated bleeding (interaction P = 5.9 × 10−5; Bonferroni‐adjusted P = 0.034). In the lowest quintile of the PGS distribution, aspirin increased major bleeding risk (HR 2.28; 95% CI: 1.45–3.58; P = 0.00036), including separate bleeding subgroups gastrointestinal (HR 3.17; 95% CI: 1.48–6.80; P = 0.0029), and intracranial bleeding (HR 4.10; 95% CI: 1.54–11.0; P = 0.0049). In contrast, in the highest quintile, aspirin was associated with lower risk of bleeding (HR 0.62; 95% CI 0.38–0.97) and reduced MACE (HR 0.66; 95% CI 0.44–0.99). Baseline serum triglycerides showed similar effect modification. These hypothesis‐generating findings suggest triglyceride‐related genetic variation may identify individuals with differential responses to aspirin.
P. Fransquet, Chenglong Yu, C. Tran et al.· Clinical pharmacology and th...· 0 citations
Longitudinal studies have shown an association between diet quality and depression. However, reverse causality, unmeasured confounding, and selection bias remained important limitations. We aim to examine the relationship between diet quality and depression in older adults while addressing these issues and explore modification role of genetic predisposition to depression and low-grade inflammation. We emulated a target trial of dietary interventions using data from the ASPREE cohort. An ultra-processed food (UPF) index and an anti-inflammatory diet measure were extracted from a food frequency questionnaire to quantify diet quality. Depressive symptoms were assessed annually with a Center for Epidemiologic Studies-Depression 10-item score of ≥8. A polygenic score was derived using the latest Psychiatric Genomics Consortium data for major depression. Systemic inflammation was assessed using circulating high-sensitivity C-reactive protein. Inverse probability treatment weighting was applied to balance measured confounders. The effects of diet quality on depressive symptoms were estimated using generalised estimating equations. A total of 7220 participants (52.7% female), aged 70+ years, were followed for a median of 5.7 years. High UPF consumption was associated with a higher risk of depressive symptoms (RR: 1.12, 95% CI: 1.03-1.21), while an anti-inflammatory diet was associated with lower depressive symptoms (RR: 0.93, 95% CI: 0.86-1.00). Genetic predisposition or low-grade inflammation did not modify the observed associations. Higher diet quality is associated with a lower risk of depressive symptoms, independent of genetic predisposition or low-grade inflammation, which may support dietary interventions as a modifiable lifestyle strategy for mental health promotion and prevention in older adults.
B. Mengist, Najmeh Davoodian, M. Lotfaliany et al.· Molecular Psychiatry· 0 citations
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