Effect of the RNF213 P.r4810k Variant on the Progression of Intracranial Artery Stenosis

Background and Objectives Intracranial 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. Methods Using 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. Results Among 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. Discussion Our findings indicated that the RNF213 p.R4810K variant increases the risk of intracranial artery stenosis progression.