Abstract
IntroductionDysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease.Patients and MethodsThe present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded.ResultsFour hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant.ConclusionOur findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.
Highlights
Dysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models
All patients with ischemic stroke or transient ischemic attack (TIA) who were admitted to our institute within 7 days of symptom onset or last-known-well were prospectively registered to the National Cerebral and Cardiovascular Center (NCVC) Stroke Registry (Yoshimoto et al, 2021)
RNF213 p.R4810K variant carriers had a higher frequency of the presence of both posterior communicating arteries (PComAs) and the absence of anterior communicating artery (AComA) compared with non-carriers, even after adjusting for differences in baseline characteristics using a stepwise method
Summary
Dysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. RING finger protein 213 (RNF213) is a susceptibility gene for large artery atherosclerosis (LAA) (Okazaki et al, 2019) as well as moyamoya disease (MMD), which is a progressive stenoocclusive disease of the circle of Willis (Kamada et al, 2011; Liu et al, 2011). This gene encodes a large protein containing two AAA + ATPases and an E3 ligase domain (Liu et al, 2011; Morito et al, 2014), and plays an important role in regulating vascular endothelial function and angiogenesis (Koizumi et al, 2016). A recent clinical study has reported that the RNF213 p.R4810K variant is associated with intracranial major artery stenosis or occlusion in anterior cerebral circulation (Matsuda et al, 2017)
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