Interaction Between Age and the NOTCH3 p.R544C Variant in Determining Ischemic Stroke Risk: Insights from the Taiwan Biobank Study of 8,588 Patients.

Genetic susceptibility to ischemic stroke may vary across the life course, yet the extent to which aging modifies the effect of specific high-risk variants remains incompletely understood. The NOTCH3 rs201118034 (p.R544C) variant, a CADASIL-related mutation with relatively high prevalence in East Asian populations, has been associated with cerebrovascular disease. We investigated whether age modifies the association between the NOTCH3 p.R544C variant and ischemic stroke risk at the population level. We integrated data from the Taiwan Biobank (TWB, 2008-2020) with the National Health Insurance Research Database (NHIRD, 2000-2020). Among 112,500 participants, 8,588 ischemic stroke cases were identified. Participants were classified as wild-type (GG) or p.R544C carriers (AG+AA). Logistic regression models were used to estimate stroke risk after adjusting for demographic characteristics, vascular comorbidities, and lifestyle factors. Effect modification by age was evaluated using interaction terms and age-genotype-stratified analyses. Overall, p.R544C carriers exhibited a higher prevalence of ischemic stroke than noncarriers (10.37% vs. 7.61%). The p.R544C variant was associated with higher odds of ischemic stroke (adjusted odds ratio [OR], 1.54; 95% confidence interval [CI], 1.24-1.90). Age was a strong determinant of stroke risk, and a significant interaction between age and genotype was observed (p for interaction = 0.02), indicating that the effect of age on ischemic stroke risk varied by genotype. In the joint age-genotype model, the highest odds of ischemic stroke were observed among AG+AA carriers aged 51-60 years (OR 7.07, 95% CI 5.08-9.82) and 61-70 years (OR 11.40, 95% CI 8.02-16.19), relative to 30-40-year-old GG carriers. These findings indicate that the association between the NOTCH3 p.R544C variant and ischemic stroke risk is age-dependent. The progressively stronger genetic effect observed in later adulthood underscores the importance of incorporating age-specific genetic susceptibility into population-based stroke risk stratification and neurogenetic epidemiology.