Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoen-cephalopathy (CADASIL) is caused by NOTCH3 gene variants and is predominantly characterized by cerebral small vessel disease. Previous studies have suggested that CADASIL may also involve the macrovascular system. This study aimed to explore the association between rare NOTCH3 variants and macrovascular lesions.

Based on the large population database UK Biobank, participants who completed distal common carotid artery ultrasonography and had available carotid intima-media thickness (CIMT) measurements were included. All participants were divided into three groups according to NOTCH3 variant carrier status: non-carriers, carriers of rare non-classical CADASIL mutations, and carriers of classical CADASIL mutations. The evaluated outcomes included CIMT parameters and cardiovascular and cerebrovascular events. Linear regression and Logistic regression models were used to analyze the association between rare NOTCH3 variants and macrovascular lesions.

A total of 512 rare NOTCH3 variants were identified, including 480 rare non-classical CADASIL mutations and 32 classical CADASIL mutations. A total of 47 664 participants were included, among whom 44 977(94.36%) were non-carriers, 2555(5.36%) carried rare non-classical CADASIL mutations, and 132(0.28%) carried classical CADASIL mutations.Logistic regression analysis showed that carriers of classical CADASIL mutations had a significantly higher risk of carotid intima-media thickening than non-carriers (OR=1.54, 95% CI: 1.07-2.22, P=0.021), as well as an elevated risk of ischemic stroke/transient ischemic attack (OR=5.51, 95% CI: 2.72-10.03, P < 0.001). No significant differences in cardiovascular events were observed between non-carriers and the two groups of rare variant carriers.

In the UK Biobank population, carriage of classical CADASIL pathogenic variants in the NOTCH3 gene is associated with an increased risk of carotid intima-media thickening and ischemic cerebrovascular events.