RNF213 p.Arg4810Lys Variant Is Associated with Higher Stenosis Progression in Asymptomatic Intracranial Artery Stenosis

Translational Stroke Research https://doi.org/10.1007/s12975-024-01309-x RESEARCH RNF213 p.Arg4810Lys Variant Is Associated with Higher Stenosis Progression in Asymptomatic Intracranial Artery Stenosis Shogo Dofuku1,2 · Satoru Miyawaki1 · Hideaki Imai1,2 · Masahiro Shimizu3 · Hiroki Hongo1 · Yuki Shinya1,4,7 · Kenta Ohara1 · Yu Teranishi1 · Hideaki Ono1,5 · Hirofumi Nakatomi1,6 · Akira Teraoka7 · Nobuhito Saito1 Received: 1 April 2024 / Revised: 23 October 2024 / Accepted: 5 November 2024 © The Author(s) 2024 Abstract Intracranial artery stenosis (ICAS) is a significant contributor to ischemic stroke, with the RNF213 p.Arg4810Lys variant identified as a related genetic factor. We explored the clinical outcomes of the RNF213 genotype in patients with asymptomatic ICAS. Between November 2011 and March 2019, 139 patients with asymptomatic ICAS were enrolled in this study. Genotyping for RNF213 p.Arg4810Lys was performed using Sanger sequencing. A comprehensive analysis was conducted to compare the RNF213 genotype with background characteristics and clinical outcomes such as ipsilateral ischemic cerebrovascular events and stenosis progression. RNF213 p.Arg4810Lys was found in 25% of cases, revealing distinct clinical features between carriers and non-carriers. The incidence of ipsilateral ischemic cerebrovascular events was 4.3% (6/139 cases), and stenosis progression was observed in 13% (18/139 cases) during a mean follow-up period of 58 months. Stenosis progression rates were notably higher in the RNF213 variant group (25.7%; 9/35 cases) than in the RNF213 wild-type group (8.7%; 9/104 cases). Cumulative stenosis progression rate was significantly higher in the RNF213 variant group than in the RNF213 wild-type group (log-rank test, P = 0.0004). Multivariate Cox regression analysis indicated a significant association between the RNF213 p.Arg4810Lys variant and an increased risk of stenosis progression (P = 0.03, odds ratio 3.2; 95% confidence interval, 1.1–9.0). The RNF213 p.Arg4810Lys variant exhibits clinical disparities in asymptomatic ICAS and is notably linked to a heightened risk of stenosis progression. These results suggest a distinct difference in the vascular stenosis mechanism associated with this variant, warranting further investigation into its clinical implications and potential mechanistic insights. Keywords Ischemic stroke · Stenosis · RNF213 Introduction * Satoru Miyawaki 1 Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan 2 Department of Neurosurgery, Tokyo Shinjuku Medical Center, Tokyo, Japan 3 Department of Neurosurgery, Kanto Neurosurgical Hospital, Kumagaya, Japan 4 Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA 5 Department of Neurosurgery, Fuji Brain Institute and Hospital, Fujinomiya, Japan 6 Department of Neurosurgery, Faculty of Medicine, The University of Kyorin, Tokyo, Japan 7 Department of Neurosurgery, Teraoka Memorial Hospital, Fukuyama, Japan Intracranial artery stenosis (ICAS) is a leading global cause of ischemic stroke [1]. Atherosclerotic changes due to lifestyle-related diseases contribute to ICAS development [2]. Factors like age, hypertension, diabetes mellitus, and dyslipidemia are correlated with ICAS prevalence, especially in regions like East and South Asia, where it comprises up to half of all ischemic stroke cases [3, 4]. Regarding genetic background, multiple single variant association studies have identified the RNF213 p.Arg4810Lys variant (rs112735431, c.14429G > A) as the most influential genetic factor linked to ICAS [5, 6]. Notably, clinical features of patients with ICAS have been reported to vary based on the RNF213 p.Arg4810Lys variant [7]. Moreover, a genomewide association study of ICAS highlighted that the RNF213 Vol.:(0123456789) Translational Stroke Research p.Arg4810Lys variant is the most significant variant associated with ICAS [8]. Aggressive medical treatment and management of the modifiable risk factors to prevent recurrence are crucial in addressing symptomatic ICAS, which leads to transient ischemic attacks and cerebral infarctions [9]. In contrast, asymptomatic ICAS has become more prominent due to widespread magnetic resonance imaging (MRI) usage [10]. However, despite increased awareness, comprehensive data on the prognosis and optimal treatment for asymptomatic ICAS are still limited [11]. Understanding the link between the genetic variant and clinical outcomes is vital for refining treatment strategies for patients with asymptomatic ICAS. Therefore, this study aimed to examine the association between the RNF213 p.Arg4810Lys variant and longterm clinical outcomes in patients with asymptomatic ICAS, focusing on the progression of ipsilateral ischemic stroke and stenosis during the follow-up period. Materials and Methods Study Population We retrospectively collected data from 408 patients diagnosed with ICAS between November 2011 and March 2019 at The University of Tokyo, Kanto Neurosurgical Hospital in Saitama, and Teraoka Memorial Hospital in Fig. 1  Flow diagram of patient selection Hiroshima. The criteria for ICAS were as follows: (i) stenosis or occlusion in major intracranial arteries on imaging findings (detailed below); (ii) age > 40 years; (iii) one or more risk factors for atherosclerosis, such as hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, arteriosclerosis obliterans, or a history of smoking; and (iv) no signs of cardiac embolism, dissection, vasculitis, or moyamoya disease (MMD) or quasi-MMD. Among these, we excluded patients with symptomatic ICAS diagnosed with cerebral infarction or transient ischemic attack in the stenotic artery area. Conversely, patients with asymptomatic ICAS were defined as those who underwent a medical checkup or exhibited unrelated symptoms such as headache and dizziness. We also excluded patients without follow-up MRA. Figure 1 shows a flow diagram of patient selection. Data on age, sex, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, arteriosclerosis obliterans, alcohol and smoking history, and family history of stroke were collected from the medical records. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive agents. Diabetes mellitus was defined as a HbA1c level ≥ 6.5% or taking anti-diabetic medications. Dyslipidemia was defined as either a high-density lipoprotein cholesterol level < 40 mg/dL, a low-density lipoprotein cholesterol level ≥ 140 mg/dL, a triglyceride level ≥ 150 mg/ dL, or receiving lipid-lowering treatment. Translational Stroke Research Imaging Findings Statistical Analysis ICAS diagnosis was primarily based on magnetic resonance angiography (MRA) (1.5 T or 3 T) or digital subtraction angiography (DSA). Two or more physicians, including at least one neurosurgeon and radiologist, reviewed the MRA images. The study excluded patient (...truncated)