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

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.118.038439Circulation. 2019;139:295–298

    Ischemic 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 IS1; 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.2,3 We 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 χ2 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±13.2 years, 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% CI, 1.90–9.28], P=3.8×10–4 in Hisayama-FSR) and in women (OR, 2.42 [95% CI, 1.69–3.45], P=1.3×10–6 in Biobank-Japan; OR, 3.73 [95% CI, 1.10–12.73], P=0.035 in Hisayama-FSR). The mean age of stroke onset was lower in carriers of the RNF213 variant than in noncarriers (56.9±10.2 years versus 65.0±9.7 years, P=6.3×10–5 in Biobank-Japan; 66.6±12.4 years versus 69.8±10.7 years, P=0.058 in Hisayama-FSR).

    For ethnic comparison, we analyzed European individuals (826 cases and 863 controls) from the INTERSTROKE study.4 In the European cohort, the maximum allele frequency was 0.0006. Although 2 heterozygote mutation carriers were identified, association testing could not be performed because of the low number of putative mutation carriers.

    Meta-analysis was performed with RevMan 5.3 software using the weighted inverse-variance/mean-difference method with a fixed-effects model. A combined meta-analysis in 3 studies showed a consistent association of the variant with all IS (OR, 1.91 [95% CI, 1.55–2.36], P=1.5×10–9) and LAA (OR, 3.58 [95% CI, 2.55–5.03], P=2.0×10–13; Figure [A]). When stratified by sex, the association was more prominent in women (OR, 1.50 [95% CI, 1.14–1.98] in men, P=0.004; OR, 2.69 [95% CI, 1.95–3.69] in women, P=1.2×10–9; Figure [B]). The mean age of stroke onset was 4.1 years lower (2.7–5.5 years) in carriers of the RNF213 variant than in noncarriers (P=1.1×10–8).

    Figure.

    Figure. Meta-analysis of the association of the RNF213 p.R4810K variant with ischemic stroke. Forest plots of odds ratios for ischemic stroke between the RNF213 p.R4810K variant carrier and noncarrier are shown by stroke subtypes (A) and sex (B). FSR indicates Fukuoka Stroke registry; IV, inverse variance method; NCVC, National Cerebral and Cardiovascular Center; and SE, standard error.

    The current study demonstrated a significant association of the RNF213 p.R4810K variant with IS, and especially with LAA, which was not reported in previous genome-wide studies because of its low allele frequency.1 The RNF213 variant is found in 20% to 30% in patients without MMD with intracranial major artery stenosis/occlusion.5 These data indicate considerable continuity between MMD and LAA, namely, RNF213-related vasculopathy. The RNF213 variant may be deficient in the vascular remodeling required for cerebral blood flow autoregulation and thus susceptible to IS. Our study has limitations. First, the primary study may have overestimated the carrier frequency because of the potential selection biases in the single-center setting. Second, no information was available regarding intracranial vessels in replication studies. Therefore, RNF213 variants labeled as LAA may have MMD, overestimating the risk of the RNF213 variant. Third, the p.R4810K variant was found only in East Asians, but was extremely rare in whites. Further studies of various RNF213 variants in various populations are needed to confirm these findings and to explore a potential therapeutic target for LAA.

    Acknowledgments

    The authors thank Dr Ahmad Khundakar for scientific input and editorial assistance. We thank the NCVC Biobank, the Tohoku Medical Megabank, the Japan Public Health Center-based Prospective study, the Japan Multi-institutional Collaborative Cohort Study, the Biobank Japan, and INTERSTROKE for providing data.

    Footnotes

    Data sharing: The data that support the findings of this study are available from the corresponding authors on reasonable request.

    https://www.ahajournals.org/journal/circ

    Shuhei Okazaki, MD, Department of Neurology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email
    Masafumi Ihara, MD, Department of Neurology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email

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