Effect of the RNF213 p.R4810K Variant on the Progression of Intracranial Artery Stenosis

Abstract

Background and ObjectivesIntracranial artery stenosis is the predominant etiology of ischemic stroke in the Asian population. Furthermore, the presence of the RNF213 p.R4810K variant, which is a susceptibility gene for moyamoya disease, increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Accordingly, we hypothesized that this genetic variant may affect the long-term outcome of intracranial artery stenosis in the East Asian population. We thus aimed to examine the effect of this variant on the long-term progression and prognosis of intracranial artery stenosis.MethodsUsing a prospective database, we identified adult patients with intracranial artery stenosis who underwent periodic MRI examinations for >5 years. We evaluated stenosis progression using a validated visual grading system. We excluded patients diagnosed with moyamoya disease at the time of initial MRI. Genotyping of RNF213 p.R4810K was performed at the end of the follow-up period.ResultsAmong 52 eligible patients, 22 (42%) were carriers of the RNF213 p.R4810K variant. The median follow-up duration was 10.3 years. During the follow-up period, progression of intracranial artery stenosis was observed in 64% variant carriers and 27% noncarriers. There was a significant association of the variant with time to progression of intracranial artery stenosis (hazard ratio [HR] 3.31, 95% CI 1.38–7.90, p = 0.007), and time to the composite endpoint of symptomatic stroke and transient ischemic attack (HR 3.70, 95% CI 1.15–11.86, p = 0.028), but not to symptomatic stroke alone (HR 2.18, 95% CI 0.62–7.74, p = 0.23). Two variant carriers with progression were newly diagnosed with moyamoya disease.DiscussionOur findings indicated that the RNF213 p.R4810K variant increases the risk of intracranial artery stenosis progression.

A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants

“… 5 , 8 We have reported that statin use is associated with slower progression of ICAS in RNF213 p.R4810K carriers. 9 Alternatively, endothelial damage could be promoted by RNF213 p.R4810K with exacerbating inflammation 10 and by PCSK9 p.E32K with the activation of apoptosis and reactive oxygen species. 11 …”

Perry Disease: Bench to Bedside Circulation and a Team Approach

“…Regarding the NOTCH3 gene, an analysis of 200,000 cases in the U.K. revealed that NOTCH3 variants are common in the general population and are also susceptibility genes for isolated stroke and vascular dementia [42]. In addition, a recent study conducted in Japan reported that the RNF213 p.R4810K variant, a susceptibility gene for moyamoya disease, is associated with intracranial arterial stenosis, resulting in atherothrombotic stroke, and impacts endovascular therapy for large vessel occlusion stroke [44,45]. Therefore, the authors proposed the concept of RNF213-related vasculopathy [46].…”

Stroke in Asia

“…Overall, there is an increased Asian-specific high prevalence of RNF213 pR4810K variant [ 93 , 94 ]. It is well known that this gene variant is closely related to progressive ICAS [ 95 ]. A synergistic relationship exists between RNF213 and additional environmental as well as genetic risk factors.…”

“…A synergistic relationship exists between RNF213 and additional environmental as well as genetic risk factors. This gene is promising in improving the understanding of disease pathogenesis and future treatment targets for both ICAS and MMD in Asia [ 95 , 96 ].…”