WSO - January 2024 - 105

1191991
WSO
International Journal of StrokeLin et al.
Research
Modifiable vascular risk factors
contribute to stroke in 1080 NOTCH3
R544C carriers in Taiwan Biobank
International Journal of Stroke
2024, Vol. 19(1) 105 -113
© 2023 World Stroke Organization
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/17474930231191991
journals.sagepub.com/home/wso
https://doi.org/10.1177/17474930231191991
Hung-Jen Lin1 , Chih-Hao Chen2 , Ming-Wei Su3, Chien-Wei Lin3,
Yu-Wen Cheng2, Sung-Chun Tang2 and Jiann-Shing Jeng2
Abstract
Background and aim: Previous studies have suggested cardiovascular risk factors increase the risk of not only common
sporadic stroke but also of stroke in patients with monogenic stroke disorders including CADASIL. We investigated
the effects of the NOTCH3 Arg544Cys (R544C) variant and associated vascular risk factors on stroke in the
Taiwanese population.
Methods: This study was conducted using data from the Taiwan Biobank, consisting of at least 130,000 Han Chinese
participants. The genotype was derived from customized genome-wide arrays for 650,000 to 750,000 single-nucleotide
polymorphisms (SNPs). Individuals with NOTCH3 R544C were subsequently matched with noncarriers based on the
propensity score at a 1:10 ratio by demographic and cardiovascular risk factors. The odds ratio (OR) for stroke or
other phenotypes in NOTCH3 R544C carriers and matched noncarriers was then calculated. Univariate and multivariate
regression analyses were performed on cardiovascular risk factors in NOTCH3 R544C carriers with and without stroke.
The polygenic risk score (PRS) model, adopted from the UK Biobank, was then applied to evaluate the role of NOTCH3
R544C in stroke.
Results: From the 114,282 participants with both genotype and questionnaire results, 1080 (0.95%) harbored the
pathogenic NOTCH3 R544C variant. When compared to the matched controls (n = 10,800), the carriers presented with
a history of stroke (OR: 2.52, 95% confidence interval (CI) (1.45, 4.37)), dementia (OR: 30.1, 95% CI (3.13, 289.43)),
and sibling history of stroke (OR: 2.48, 95% CI (1.85, 3.34)) phenotypes. The risk of stroke increased with every 10-year
increase in age (p = 0.006, Cochran-Mantel-Haenszel test). Among NOTCH3 R544C carriers, 16 (1.3%) of the 1080 carriers
with a stroke history were older, male, and more likely to have hypertension, diabetes, dyslipidemia, and a family
history of stroke. In the stepwise multivariate analysis, hypertension (OR: 11.28, 95% CI (3.54, 43.3)) and diabetes mellitus
(OR: 4.10, 95% CI (1.31, 12.4)) were independently associated with stroke. Harboring the NOTCH3 R544C variant in
the Taiwan Biobank is comparable with a 6.74 standard deviations increase in individual's polygenic risk score for stroke.
Conclusion: While the NOTCH3 R544C variant alone increased the risk of stroke, modifiable vascular risk factors also
played a role in the occurrence of stroke in Taiwanese community-dwelling individuals carrying the NOTCH3 variant.
Keywords
CADASIL, epidemiology, stroke, genetic disorders, stroke prevalence, risk factors
Received: 19 May 2023; accepted: 17 July 2023
Introduction
Cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) due to
cysteine-altering NOTCH3 variants is the most common
hereditary stroke syndrome.1 The patients with CADASIL
exhibit broad-spectrum phenotypes, including stroke, cognitive
deficit, gait disturbance, migraine with aura, and
1Department of Medical Education, National Taiwan University Hospital,
Taipei
2Department of Neurology, National Taiwan University Hospital, Taipei
3Institute of Biomedical Sciences, Academia Sinica, Taipei
Corresponding author:
Sung-Chun Tang, Department of Neurology, National Taiwan University
Hospital, No. 7, Chung-Shan South Road, Taipei 100225.
Email: tangsc@ntuh.gov.tw
International Journal of Stroke, 19(1)
http://www.sagepub.com/journals-permissions https://www.doi.org/10.1177/17474930231191991 http://journals.sagepub.com/home/wso
WSO - January 2024

Table of Contents for the Digital Edition of WSO - January 2024
