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.