Moyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis

◼ moyamoya disease ◼ RING finger domains ◼ stroke I schemic stroke (IS) is the leading cause of disability and early death in Asia, where large-artery atherosclerosis (LAA) attributable to intracranial stenosis is the predominant etiology.Recently, a large transethnic genome-wide association study identified 32 loci associated with IS 1 ; however, Asian-specific genetic determinants remain unknown.Moyamoya disease (MMD), a rare cerebrovascular disease endemic in East Asia, is associated with a susceptibility gene RNF213, and its dysregulation experimentally impairs cerebral perfusion. 2,3We hypothesized a more general role of RNF213 in IS and examined the association of the p.R4810K variant of the RNF213 gene, the founder variant for MMD for Japanese, Korean, and Chinese, 2 with IS and its subtypes.In this 2-stage case-control study, we analyzed data from 3 independent Japanese population studies with a total of 46 958 individuals of East Asian ancestry (17 752 cases and 29 206 controls).All study participants provided written informed consent, and the responsible ethics committees and the local ethics committee of the National Cerebral and Cardiovascular Center approved the study.Variables were compared by using the Student t test and χ 2 test as appropriate.Stroke subtypes were classified according to TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment).In the primary stage, we examined the p.R4810K genotype using a single hospital-based population with clinical and radiological data (NCVC Biobank: 383 noncardioembolic stroke cases and 1011 controls), excluding patients with MMD (n=12).The RNF213 p.R4810K variant was found in 5.2% of patients with noncardioembolic stroke and in 2.1% of controls (odds ratio [OR], 2.60 [95% CI, 1.39-4.85],P=0.0019).When stratified by subtypes, only LAA was significantly associated with the variant (OR, 5.19 [95% CI, 2.53-10.64],P=2.6×10 -6 ).The mean age of stroke onset was lower in the variant carriers than noncarriers (58.1±15.5 years versus 69.1±13.2years, P=0.0003).The variant carriers included more women (55.0%versus 27.3%, P=0.011), and showed greater frequency of intracranial anterior circulation stenosis (60.0%versus 27.3%, P=0.004).We investigated whether the significant association was replicable.The p.R4810K genotypes were derived from genome-wide genotyping data in Biobank-Japan (16 256 IS cases and 27 294 controls), and the Hisayama and the Fukuoka Stroke Registry (FSR) study (1113 cases and 901 controls).We investigated the association between RNF213 R4810K and IS by imputed allele dosage of R4810K and fitted to logistic regression model with additive genetic model. 1 In the replication stage, the variant was found in 2.3% and 3.8% of patients with ischemic stroke and in 1.3% of both controls in the Biobank-Japan and Hisayama-FSR.In comparison with controls, the carrier frequency was significantly higher in all IS cases (OR, 1.77 [95% CI, 1.40-2.24],P=1.6×10 -6 in Biobank-Japan; OR, 2.90 [95% CI, 1.39-6.04],P=0.0045 in Hisayama-FSR), especially in those with LAA (OR, 3.10 [95% CI, 1.98-4.84],P=6.9×10 -7 in Biobank-Japan; OR, 4.20 [95%