The NOTCH3 p.R544C variant was associated with higher odds of ischemic stroke in Taiwan Biobank participants, and this association was age-dependent (p for interaction = 0.02), with the highest odds in carriers aged 51-70 years.
Among 112,500 Taiwan Biobank participants linked to national insurance records, 8,588 ischemic stroke cases were identified.
Ischemic stroke was more prevalent among NOTCH3 p.R544C carriers than noncarriers.
The p.R544C variant was independently associated with higher odds of ischemic stroke after adjustment.
Age was a strong determinant of ischemic stroke risk, and age significantly modified the genotype-stroke association.
In the joint age-genotype model, odds of ischemic stroke were highest in carriers aged 51-70 years relative to 30-40-year-old wild-type individuals.
The authors conclude the genetic effect of p.R544C strengthens progressively in later adulthood, supporting age-specific genetic risk stratification.
This study looked at a genetic variant in the NOTCH3 gene, called p.R544C, which is relatively common in East Asian populations and is related to a hereditary small-vessel brain disease. Using data from over 112,500 people in the Taiwan Biobank linked to national health insurance records, the researchers compared ischemic stroke rates in people with and without the variant. About 10.4% of carriers had had an ischemic stroke, compared with 7.6% of non-carriers. After accounting for other factors such as vascular conditions and lifestyle, carriers had about 1.5 times the odds of stroke. The effect of the variant was not the same at all ages. The statistical analysis showed that age and genotype interacted, and the largest differences appeared in middle and older adulthood. Carriers aged 51-60 had about 7 times the odds, and those aged 61-70 had about 11 times the odds, of stroke compared with non-carriers aged 30-40. These comparisons use a young reference group, so they reflect the combined effect of age and genotype rather than the variant alone. This research suggests that the stroke risk linked to this variant grows with age, and that age may be worth considering when assessing genetic risk in populations where the variant is common. Because the study is observational and based on a biobank, it shows associations rather than proving cause, and it cannot say how individuals should be tested or treated.
Liaw Y, Nfor O, Chen C, Hsu S, Liaw Y, Liaw Y. (2026). Interaction Between Age and the NOTCH3 p.R544C Variant in Determining Ischemic Stroke Risk: Insights from the Taiwan Biobank Study of 8,588 Patients.. International journal of medical sciences. https://doi.org/10.7150/ijms.132147