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Andrew M Tonkin

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Open access Aug 2026

Circulating biomarkers and polygenic scores for cardiovascular risk prediction in healthy older adults: differential and complementary contributions.

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

Open access Aug 2026

Triglyceride Polygenic Score Identifies Individuals Who May Respond Differently to Aspirin in Primary Prevention

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