Association of Rare NOTCH3 Variants with Prevalent and Incident Stroke and Dementia in the General Population
Pei Wang1, Ming Yao1, Jing Yuan1, Fei Han1, Feifei Zhai1, Dingding Zhang2, Lixin Zhou1, Jun Ni1, Shuyang Zhang3, Liying Cui1, Yicheng Zhu1
1Department of Neurology, 2Medical Research Center, 3Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Objective:
This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes.
Background:
Rare NOTCH3 variants have been identified in a considerable proportion of the general population and are associated with imaging changes related to cerebral small vessel disease. In addition, previous studies have found that rare NOTCH3 variants are significantly enriched in Alzheimer’s disease patients compared to controls.
Design/Methods:
In the prospective community-based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow-up analysis, 1007 participants were included in the stroke analysis and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency <1%.
Results:
A total of 137 rare NOTCH3 carriers were enrolled in the baseline study. At baseline, rare NOTCH3 variant carriers had higher rates of stroke (8.8% vs 5.6%) and dementia (2.9% vs 0.8%) compared to non-carriers. After adjustment for associated risk factors, the EGFr-involving rare NOTCH3 variants were associated with a higher risk of prevalent stroke (odds ratio, 2.863 [95% CI, 1.334-6.143]; p=0.028) and dementia (odds ratio, 11.155 [95% CI, 1.601-77.745]; p=0.030). In addition, the rare NOTCH3 variant carriers had a higher rate of carotid plaques (odds ratio, 1.844 [95% CI, 1.158-2.937]; p=0.040). After 5 years of follow-up, we did not find that the rare NOTCH3 variants increased the risk of incident stroke and dementia. There were no statistically significant differences in the cognitive scale scores at baseline or in the changes over the five years.
Conclusions:
Rare NOTCH3 EGFr-involving variants are genetic risk factors for stroke and dementia in the general Chinese population.