Sultana Monira Hussain

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.

BACKGROUND: Low-dose aspirin is no longer recommended for routine primary prevention in older adults due to bleeding risks outweighing vascular benefits. We hypothesized that an integrative polygenic score (iPGS) could identify a subgroup of older individuals who derive net benefit from aspirin for the primary prevention of ischemic stroke. METHODS: We performed post hoc analysis of the ASPREE randomized, placebo-controlled trial (Aspirin in Reducing Events in the Elderly) of daily 100-mg aspirin, in 12 031 genotyped participants of European ancestry aged >70 years without prior cardiovascular disease. The iPGS was derived from >1.2 million variants and evaluated both continuously and by quintiles. Cox models assessed associations between polygenic risk, ischemic stroke, and major bleeding events, and tested the interaction between the iPGS and treatment allocation, with adjustment for baseline lifestyle and clinical covariates. RESULTS: The mean age of participants was 75.1 years, and 54.9% were women. Over a median of 4.6 years, 187 ischemic strokes and 373 major bleeds occurred, including 101 intracranial bleeds (46 hemorrhagic strokes). Each 1-SD increase in the iPGS was associated with higher incident ischemic stroke risk (hazard ratio, 1.39 [95% CI, 1.20–1.62]). An interaction between the continuous iPGS and aspirin allocation was observed for ischemic stroke ( P =0.04) but not major bleeding. In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (hazard ratio, 0.49 [95% CI, 0.28–0.85]) without significantly increasing major bleeding (hazard ratio, 1.15 [95% CI, 0.71–1.88]). No benefit was observed in the overall cohort or in lower-risk quintiles. CONCLUSIONS: Among older adults, high polygenic risk identifies individuals who may experience substantial stroke reduction with aspirin, with no excess bleeding. These findings raise the possibility that genomic risk stratification may enable targeted aspirin use for the primary prevention of ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01038583.

Objective: Reports have linked both high and low serum uric acid (SUA) levels to adverse health outcomes. This study aimed to establish a reference interval for SUA in older adults and assessed its association with clinically relevant outcomes in relatively healthy, community‐dwelling individuals aged ≥70 years old. Methods: The study used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. In Australia, 11,878 ASPREE participants had baseline SUA measurements (median age 74 years old). The study sample (n = 11,446; 55% women) comprised individuals with baseline SUA measurements, excluding those on urate‐lowering medication. The reference sample (n = 10,501; 55% women) was established after further exclusion of participants with impaired renal function, defined as an estimated glomerular filtration rate 2 . Reference intervals (2.5th and 97.5th percentile) were stratified by sex, and Cox proportional hazard models assessed associations between SUA levels and relevant clinical outcomes. Results: SUA reference intervals were 0.24 to 0.54 mmol/L for men and 0.19 to 0.48 mmol/L for women. After adjusting for potential confounders, no association was observed between SUA levels and all‐cause mortality, disability‐free survival, cardiovascular disease, major adverse cardiovascular events, cancer incidence and mortality, or dementia in either the study or reference samples. In women, however, low SUA levels were associated with an increased risk of fractures (hazard ratio 1.23; 95% confidence interval 1.04–1.46). Conclusion: Although previous reports have linked abnormal SUA levels to adverse health outcomes, our findings show no associations within the reference range, except for an increased fracture risk among women with low SUA levels.

Variants in the homeostatic iron regulator (HFE) gene are prevalent among individuals of European ancestry and have been linked to an increased risk of dementia. This study aimed to evaluate the effects of HFE p.Cys282Tyr and p.His63Asp variants on serum ferritin levels and the incidence of dementia in a cohort of initially healthy older adults. This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly trial. Participants had no history of cardiovascular disease, dementia, or cognitive decline at enrollment. Genotyping for HFE p.Cys282Tyr and p.His63Asp variants was conducted using microarrays, and baseline serum ferritin concentrations were measured in peripheral blood samples. Dementia diagnoses were confirmed by an adjudication committee over a median follow-up of 6.4 years. Associations were evaluated using Cox proportional hazards models adjusted for related covariates. The study included 12,174 unrelated, healthy participants of European ancestry aged 70 years or older, comprising 5,583 men (45.9%) and 6,591 women (54.1%). The median age was 73.7 years (interquartile range [IQR]: 71.6-76.9) for men and 73.9 years (IQR: 71.7-77.5) for women. Compared with the wild-type group, men with p.Cys282Tyr+/+ (p = 0.048) and p.Cys282Tyr+/p.His63Asp + genotypes (p < 0.001) had significantly higher baseline ferritin levels. Women with p.His63Asp+/+ (p = 0.015) and p.Cys282Tyr+/p.His63Asp+ (p < 0.001) genotypes also exhibited elevated ferritin levels. No significant association was observed between baseline serum ferritin levels and dementia risk. However, men with p.His63Asp+/+ genotype had a significantly higher risk of incident dementia (adjusted hazard ratio = 2.39, 95% CI 1.25-4.57, p = 0.009) compared with those without HFE variations. This association was not observed in women. Among initially healthy older adults, HFE p.His63Asp homozygosity was associated with a higher risk of incident dementia in men but not women. These findings highlight a potential sex-specific genetic risk factor for dementia and warrant further research into the underlying mechanisms linking p.His63Asp and dementia.

Background: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly ordered tests in general medical practice. However, their distribution and significance in older adults are understudied. As such, we aimed to evaluate sex-stratified distribution of both ALT and AST in older adults (≥70 years) and assess for associations with mortality. Methods: Post-hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) randomized, placebo-controlled trial of daily low-dose aspirin for initially relatively healthy older persons. Univariate analysis and multiple logistic regression were used to explore baseline characteristics. Cox regression and restricted cubic splines were used to examine links between transaminase levels and mortality. Results: Of the 11 853 participants with ALT and AST levels, 1 054 (8.9%) deaths were recorded over a median of 6.4 (interquartile range [IQR] 5.4–7.6) years. For ALT, the lowest quintiles for males and females were 6–15 and 5–13 U/L, respectively; for AST, the lowest quintiles were 8–18 and 7–17 U/L, respectively. On both univariate and models adjusted for covariates including age, body mass index, frailty, diabetes, and kidney disease, males and females in the lowest quintile of ALT had an increased hazard of mortality (aHR 1.51 [95% confidence interval {CI} 1.14–1.99] and aHR 1.39 [95% CI 1.03–1.88], respectively). For the lowest quintile of AST, only males were at increased risk (aHR 1.33 [95% CI 1.04–1.70]). Associations remained significant when removing outliers. Conclusions: Low ALT levels independently confer an increased hazard of mortality for older males and females; low AST only affected older male survival. Further evaluation of mechanisms would be worthwhile, and re-evaluating the lower limit of normal for ALT in older adults should be considered.