Voltar
Revisão Acesso aberto Revisado por pares
BIBTEX RIS

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

2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 2 Linguagem: Inglês

10.1161/circulationaha.118.038439

ISSN

1524-4539

Autores

Shuhei Okazaki, Takaaki Morimoto, Yoichiro Kamatani, Teppei Kamimura, Hatasu Kobayashi, Kouji H. Harada, Tsutomu Tomita, Aya Higashiyama, Jun Takahashi, Jyoji Nakagawara, Masatoshi Koga, Ḱazunori Toyoda, Kazuo Washida, Satoshi Saitô, Atsushi Takahashi, Makoto Hirata, Koichi Matsuda, Hideki Mochizuki, Michael Chong, Guillaume Paré, Martin O’Donnell, Tetsuro Ago, Jun Hata, Toshiharu Ninomiya, Martin Dichgans, Stéphanie Debette, Michiaki Kubo, Akio Koizumi, Masafumi Ihara,

Tópico(s)

Aortic Disease and Treatment Approaches

Resumo

HomeCirculationVol. 139, No. 2Moyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBMoyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis Shuhei Okazaki, MD, Takaaki Morimoto, MD, Yoichiro Kamatani, MD, Teppei Kamimura, MD, Hatasu Kobayashi, MD, Kouji Harada, PhD, MPH, Tsutomu Tomita, MD, Aya Higashiyama, MD, Jun C. Takahashi, MD, Jyoji Nakagawara, MD, Masatoshi Koga, MD, Kazunori Toyoda, MD, Kazuo Washida, MD, Satoshi Saito, MD, Atsushi Takahashi, PhD, Makoto Hirata, MD, Koichi Matsuda, MD, Hideki Mochizuki, MD, Michael Chong, MSc, Guillaume Paré, MD, Martin O'Donnell, PhD, Tetsuro Ago, MD, Jun Hata, MD, Toshiharu Ninomiya, MD, Martin Dichgans, MD, Stéphanie Debette, MD, Michiaki Kubo, MD, Akio Koizumi, MD and Masafumi Ihara, MD Shuhei OkazakiShuhei Okazaki Shuhei Okazaki, MD, Department of Neurology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email E-mail Address: [email protected] Department of Neurology (S.O., T.K., K.W., S.S., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan. Department of Neurology, Osaka University Graduate School of Medicine, Japan (S.O., H.M.). , Takaaki MorimotoTakaaki Morimoto Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Japan (T.M., H.K., K.H., A.K.). , Yoichiro KamataniYoichiro Kamatani Laboratory for Statistical Analysis (Y.K., A.T.), Kanagawa, Japan. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Japan (Y.K.). , Teppei KamimuraTeppei Kamimura Department of Neurology (S.O., T.K., K.W., S.S., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Hatasu KobayashiHatasu Kobayashi Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Japan (T.M., H.K., K.H., A.K.). Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan (H.K.). , Kouji HaradaKouji Harada Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Japan (T.M., H.K., K.H., A.K.). , Tsutomu TomitaTsutomu Tomita NCVC Biobank (T.T., A.H.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Aya HigashiyamaAya Higashiyama NCVC Biobank (T.T., A.H.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Jun C. TakahashiJun C. Takahashi Department of Neurosurgery (J.C.T., J.N.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Jyoji NakagawaraJyoji Nakagawara Department of Neurosurgery (J.C.T., J.N.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Masatoshi KogaMasatoshi Koga Department of Cerebrovascular Medicine (M. Koga, K.T.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Kazunori ToyodaKazunori Toyoda Department of Cerebrovascular Medicine (M. Koga, K.T.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Kazuo WashidaKazuo Washida Department of Neurology (S.O., T.K., K.W., S.S., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Satoshi SaitoSatoshi Saito Department of Neurology (S.O., T.K., K.W., S.S., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan. , Atsushi TakahashiAtsushi Takahashi Department of Genomic Medicine, Research Institute (A.T.), National Cerebral and Cardiovascular Center, Osaka, Japan. Laboratory for Statistical Analysis (Y.K., A.T.), Kanagawa, Japan. , Makoto HirataMakoto Hirata Institute of Medical Science, The University of Tokyo, Japan (M.H.). , Koichi MatsudaKoichi Matsuda Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan (K.M.). , Hideki MochizukiHideki Mochizuki Department of Neurology, Osaka University Graduate School of Medicine, Japan (S.O., H.M.). , Michael ChongMichael Chong Population Health Research Institute, McMaster University, Hamilton, Canada (M.C., G.P.). , Guillaume ParéGuillaume Paré Population Health Research Institute, McMaster University, Hamilton, Canada (M.C., G.P.). , Martin O'DonnellMartin O'Donnell Health Research Board Clinical Research Facility, National University of Ireland Galway, and University Hospital Galway, Galway, Ireland (M.O.). , Tetsuro AgoTetsuro Ago Department of Medicine and Clinical Science (T.A.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. , Jun HataJun Hata Department of Epidemiology and Public Health (J.H., T.N.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. , Toshiharu NinomiyaToshiharu Ninomiya Department of Epidemiology and Public Health (J.H., T.N.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. , Martin DichgansMartin Dichgans Institute for Stroke and Dementia Research, Ludwig-Maximilians-University Munich, Medical Center, Munich, Germany (M.D.). Munich Cluster of Systems Neurology (SyNergy), Munich, Germany (M.D.). , Stéphanie DebetteStéphanie Debette Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, France (S.D.). , Michiaki KuboMichiaki Kubo RIKEN Center for Integrative Medical Sciences (M. Kubo), Kanagawa, Japan. , Akio KoizumiAkio Koizumi Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Japan (T.M., H.K., K.H., A.K.). and Masafumi IharaMasafumi Ihara Masafumi Ihara, MD, Department of Neurology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email E-mail Address: [email protected] Department of Neurology (S.O., T.K., K.W., S.S., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan. Originally published7 Jan 2019https://doi.org/10.1161/CIRCULATIONAHA.118.038439Circulation. 2019;139:295–298Ischemic 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).Download figureDownload PowerPointFigure. 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.AcknowledgmentsThe 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.Sources of FundingThis study was supported by the Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center, and by a Grant-in-Aid from the Ministry of Culture Science and Sports of Japan (JP17H06397).DisclosuresDr Akio Koizumi has a patent for RNF213 (P130009545).FootnotesData sharing: The data that support the findings of this study are available from the corresponding authors on reasonable request.https://www.ahajournals.org/journal/circShuhei Okazaki, MD, Department of Neurology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email [email protected]ac.jpMasafumi Ihara, MD, Department of Neurology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email [email protected]go.jpReferences1. Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Bis JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Björkegren JLM, Codoni V, Civelek M, Smith NL, Trégouët DA, Christophersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliott P, Chambers JC, Takeuchi F, Johnson AD, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, Dichgans M, Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, Hoed MD, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Amin N, Aparicio HS, Arnett DK, Attia J, Beiser AS, Berr C, Buring JE, Bustamante M, Caso V, Cheng YC, Choi SH, Chowhan A, Cullell N, Dartigues JF, Delavaran H, Delgado P, Dörr M, Engström G, Ford I, Gurpreet WS, Hamsten A, Heitsch L, Hozawa A, Ibanez L, Ilinca A, Ingelsson M, Iwasaki M, Jackson RD, Jood K, Jousilahti P, Kaffashian S, Kalra L, Kamouchi M, Kitazono T, Kjartansson O, Kloss M, Koudstaal PJ, Krupinski J, Labovitz DL, Laurie CC, Levi CR, Li L, Lind L, Lindgren CM, Lioutas V, Liu YM, Lopez OL, Makoto H, Martinez-Majander N, Matsuda K, Minegishi N, Montaner J, Morris AP, Muiño E, Müller-Nurasyid M, Norrving B, Ogishima S, Parati EA, Peddareddygari LR, Pedersen NL, Pera J, Perola M, Pezzini A, Pileggi S, Rabionet R, Riba-Llena I, Ribasés M, Romero JR, Roquer J, Rudd AG, Sarin AP, Sarju R, Sarnowski C, Sasaki M, Satizabal CL, Satoh M, Sattar N, Sawada N, Sibolt G, Sigurdsson Á, Smith A, Sobue K, Soriano-Tárraga C, Stanne T, Stine OC, Stott DJ, Strauch K, Takai T, Tanaka H, Tanno K, Teumer A, Tomppo L, Torres-Aguila NP, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Völzke H, Wakai K, Weir D, Williams SR, Wolfe CDA, Wong Q, Xu H, Yamaji T, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, Dichgans M; AFGen Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; International Genomics of Blood Pressure (iGEN-BP) Consortium; INVENT Consortium; STARNET; BioBank Japan Cooperative Hospital Group; COMPASS Consortium; EPIC-CVD Consortium; EPIC-InterAct Consortium; International Stroke Genetics Consortium (ISGC); METASTROKE Consortium; Neurology Working Group of the CHARGE Consortium; NINDS Stroke Genetics Network (SiGN); UK Young Lacunar DNA Study; MEGASTROKE Consortium; MEGASTROKE Consortium. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018; 50:524–537. doi: 10.1038/s41588-018-0058-3CrossrefMedlineGoogle Scholar2. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M, Miyamoto S, Nagata K, Hashimoto N, Koizumi A. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.PLoS One. 2011; 6:e22542. doi: 10.1371/journal.pone.0022542CrossrefMedlineGoogle Scholar3. Morimoto T, Enmi JI, Hattori Y, Iguchi S, Saito S, Harada KH, Okuda H, Mineharu Y, Takagi Y, Youssefian S, Iida H, Miyamoto S, Ihara M, Kobayashi H, Koizumi A. Dysregulation of RNF213 promotes cerebral hypoperfusion.Sci Rep. 2018; 8:3607. doi: 10.1038/s41598-018-22064-8CrossrefMedlineGoogle Scholar4. O'Donnell M, Xavier D, Diener C, Sacco R, Lisheng L, Zhang H, Pias P, Truelsen T, Chin SL, Rangarajan S, Devilliers L, Damasceno A, Mondo C, Lanas F, Avezum A, Diaz R, Varigos J, Hankey G, Teal P, Kapral M, Ryglewicz D, Czlonkowska A, Skowronska M, Lopez-Jaramillo P, Dans T, Langhorne P, Yusuf S; INTERSTROKE investigators. Rationale and design of INTERSTROKE: a global case-control study of risk factors for stroke.Neuroepidemiology. 2010; 35:36–44. doi: 10.1159/000306058CrossrefMedlineGoogle Scholar5. Miyawaki S, Imai H, Shimizu M, Yagi S, Ono H, Mukasa A, Nakatomi H, Shimizu T, Saito N. Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion.Stroke. 2013; 44:2894–2897. doi: 10.1161/STROKEAHA.113.002477LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ohara M, Yoshimoto T, Okazaki S, Gon Y, Todo K, Sasaki T, Takasugi J, Ohara N, Ihara M and Mochizuki H (2022) RNF213 p.R4810K Variant Carriers with Intracranial Arterial Stenosis Have a Low Atherosclerotic Burden, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.63379, 29:11, (1655-1662), Online publication date: 1-Nov-2022. Yoshimoto T, Tanaka K, Koge J, Saito S, Yamagami H, Nakaoku Y, Ogata S, Nishimura K, Yamaguchi E, Chiba T, Kawakami D, Shiozawa M, Kamogawa N, Ohta T, Satow T, Inoue M, Hattori Y, Washida K, Kataoka H, Chung J, Bang O, Toyoda K, Koga M, Maruyama H and Ihara M (2022) Impact of the RNF213 p.R4810K Variant on Endovascular Therapy for Large‐Vessel Occlusion Stroke, Stroke: Vascular and Interventional Neurology, 2:6, Online publication date: 1-Nov-2022.Yamaguchi E, Yoshimoto T, Ogura S, Saito K, Saito S, Hattori Y, Wasida K, Nishimura K, Toyoda K, Koga M and Ihara M (2022) Association of the RNF213 p.R4810K Variant With the Outer Diameter of Cervical Arteries in Patients With Ischemic Stroke, Stroke: Vascular and Interventional Neurology, 2:6, Online publication date: 1-Nov-2022.Ok T, Jung Y, Kim J, Park S, Park G, Lee S and Lee K (2022) R4810K Variant in Suspected Unilateral Moyamoya Disease Predicts Contralateral Progression, Journal of the American Heart Association, 11:15, Online publication date: 2-Aug-2022. Ihara M, Yamamoto Y, Hattori Y, Liu W, Kobayashi H, Ishiyama H, Yoshimoto T, Miyawaki S, Clausen T, Bang O, Steinberg G, Tournier-Lasserve E and Koizumi A (2022) Moyamoya disease: diagnosis and interventions, The Lancet Neurology, 10.1016/S1474-4422(22)00165-X, 21:8, (747-758), Online publication date: 1-Aug-2022. Dofuku S, Sonehara K, Miyawaki S, Sakaue S, Imai H, Shimizu M, Hongo H, Shinya Y, Ohara K, Teranishi Y, Okano A, Ono H, Nakatomi H, Teraoka A, Yamamoto K, Maeda Y, Nii T, Kishikawa T, Suzuki K, Hirata J, Takahashi M, Matsuda K, Kumanogoh A, Matsuda F, Okada Y and Saito N (2022) Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study, Translational Stroke Research, 10.1007/s12975-022-01049-w Ahmed S, Habu T, Kim J, Okuda H, Oikawa S, Murata M, Koizumi A and Kobayashi H (2022) Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2022.04.007, 609, (62-68), Online publication date: 1-Jun-2022. Liu M, Sariya S, Khasiyev F, Tosto G, Dueker N, Cheung Y, Wright C, Sacco R, Rundek T, Elkind M and Gutierrez J (2022) Genetic determinants of intracranial large artery stenosis in the northern Manhattan study, Journal of the Neurological Sciences, 10.1016/j.jns.2022.120218, 436, (120218), Online publication date: 1-May-2022. Debette S and Markus H (2022) Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives, Circulation Research, 130:8, (1095-1111), Online publication date: 15-Apr-2022.Roy V, Ross J, Pépin R, Cortez Ghio S, Brodeur A, Touzel Deschênes L, Le-Bel G, Phillips D, Milot G, Dion P, Guérin S, Germain L, Berthod F, Auger F, Rouleau G, Dupré N and Gros-Louis F (2022) Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function, Stroke, 53:4, (1263-1275), Online publication date: 1-Apr-2022. Luo Y, Cao Z, Wu S and Sun X (2022) Ring Finger Protein 213 in Moyamoya Disease With Pulmonary Arterial Hypertension: A Mini-Review, Frontiers in Neurology, 10.3389/fneur.2022.843927, 13 He S, Ye X, Duan R, Zhao Y, Wei Y, Wang Y, Liu Z, Hao X, Chen X, Hao Q, Wang H, Zhao Y, Wang R and Tahmasbpour E (2022) Epigenome-Wide Association Study Reveals Differential Methylation Sites and Association of Gene Expression Regulation with Ischemic Moyamoya Disease in Adults, Oxidative Medicine and Cellular Longevity, 10.1155/2022/7192060, 2022, (1-13), Online publication date: 24-Mar-2022. Fukuma K, Yamagami H, Ihara M, Tanaka T, Miyata T, Miyata S, Kokame K, Nishimura K, Nakaoku Y, Yamamoto H, Hayakawa M, Kamiyama K, Enomoto Y, Itabashi R, Furui E, Manabe Y, Ezura M, Todo K, Hashikawa K, Uchiyama S, Toyoda K and Nagatsuka K (2022) P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.63369, . Song X and Li Z (2021) Co-existing of craniofacial fibrous dysplasia and cerebrovascular diseases: a series of 22 cases and review of the literature, Orphanet Journal of Rare Diseases, 10.1186/s13023-021-02102-x, 16:1, Online publication date: 1-Dec-2021. Tabara Y, Yamada H, Setoh K, Matsukawa M, Takahashi M, Kawaguchi T, Nakayama T, Matsuda F and Kosugi S (2021) The association between the Moyamoya disease susceptible gene RNF213 variant and incident cardiovascular disease in a general population: the Nagahama study, Journal of Hypertension, 10.1097/HJH.0000000000002964, 39:12, (2521-2526), Online publication date: 1-Dec-2021. Mineharu Y and Miyamoto S (2021) RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability, Frontiers in Neurology, 10.3389/fneur.2021.687088, 12 Eto F, Yoshimoto T, Okazaki S, Nishimura K, Ogura S, Yamaguchi E, Fukuma K, Saito S, Washida K, Koga M, Toyoda K, Morimoto T, Maruyama H, Koizumi A and Ihara M (2021) RNF213 p.R4810K (c.14429G > A) Variant Determines Anatomical Variations of the Circle of Willis in Cerebrovascular Disease, Frontiers in Aging Neuroscience, 10.3389/fnagi.2021.681743, 13 Cho B, Nannoni S, Harshfield E, Tozer D, Gräf S, Bell S and Markus H (2021) NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants , Journal of Neurology, Neurosurgery & Psychiatry, 10.1136/jnnp-2020-325838, 92:7, (694-701), Online publication date: 1-Jul-2021. Wang X, Zhang Z, Wang Y, Zou Z, Ta N, Hao F, Shang M, Li D, Zeng F, Han C, Nie F, Bao X, Yang Y, Wang H, Liang M, Yang R, Ou L, Wen L, Yang Z, Liu W and Duan L (2021) Clinical and Genetic Risk Factors of Long-Term Outcomes after Encephaloduroarteriosynangiosis in Moyamoya Disease in China, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2021.105847, 30:7, (105847), Online publication date: 1-Jul-2021. Leng X, Hurford R, Feng X, Chan K, Wolters F, Li L, Soo Y, Wong K, Mok V, Leung T and Rothwell P (2021) Intracranial arterial stenosis in Caucasian versus Chinese patients with TIA and minor stroke: two contemporaneous cohorts and a systematic review, Journal of Neurology, Neurosurgery & Psychiatry, 10.1136/jnnp-2020-325630, 92:6, (590-597), Online publication date: 1-Jun-2021. Ye F, Wang T, Yin H, Li J, Li H, Guo T, Zhang X, Yang T, Jie L, Wu X, Li Q and Sheng W (2021) Development and Validation of a Nomogram to Predict the Individual Future Stroke Risk for Adult Patients With Moyamoya Disease: A Multicenter Retrospective Cohort Study in China, Frontiers in Neurology, 10.3389/fneur.2021.669025, 12 Pinard A, Fiander M, Cecchi A, Rideout A, Azouz M, Fraser S, McNeely P, Walling S, Novara S, Hurst A, Guo D, Parkash S, Bamshad M, Nickerson D, Vandersteen A and Milewicz D (2021) Association of De Novo RNF213 Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy , Neurology, 10.1212/WNL.0000000000011653, 96:13, (e1783-e1791), Online publication date: 30-Mar-2021. Kim H, Choi E, Chung J, Kim J, Kim Y, Seo W, Kim G and Bang O (2020) Role of the RNF213 Variant in Vascular Outcomes in Patients With Intracranial Atherosclerosis, Journal of the American Heart Association, 10:1, Online publication date: 5-Jan-2021. Nomura S, Akagawa H, Yamaguchi K, Kawashima A and Kawamata T (2021) RNF213 and Clinical Feature Moyamoya Disease: Current Knowledge and Future Perspectives, 10.1007/978-981-33-6404-2_5, (61-72), . Xiang L, Zhang T, Zhang B, Zhang C, Cui W and Yue W (2020) Positive syphilis serology contributes to intracranial stenosis in ischemic stroke patients, Brain and Behavior, 10.1002/brb3.1906, 11:1, Online publication date: 1-Jan-2021. Hongo H, Miyawaki S, Imai H, Shimizu M, Yagi S, Mitsui J, Ishiura H, Yoshimura J, Doi K, Qu W, Teranishi Y, Okano A, Ono H, Nakatomi H, Shimizu T, Morishita S, Tsuji S and Saito N (2020) Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis, Scientific Reports, 10.1038/s41598-020-68888-1, 10:1, Online publication date: 1-Dec-2020. Kim H, Choi E, Chung J, Kim J, Kim Y, Seo W, Kim G and Bang O (2020) Luminal and Wall Changes in Intracranial Arterial Lesions for Predicting Stroke Occurrence, Stroke, 51:8, (2495-2504), Online publication date: 1-Aug-2020. Bang O, Chung J, Kim D, Won H, Yeon J, Ki C, Shin H, Kim J, Hong S, Kim D and Koizumi A (2019) Moyamoya Disease and Spectrums of RNF213 Vasculopathy, Translational Stroke Research, 10.1007/s12975-019-00743-6, 11:4, (580-589), Online publication date: 1-Aug-2020. Wang X, Wang Y, Nie F, Li Q, Zhang K, Liu M, Yang L, Zhang Q, Liu S, Zeng F, Shang M, Liang M, Yang Y, Liu X and Liu W (2020) Association of Genetic Variants With Moyamoya Disease in 13 000 Individuals, Stroke, 51:6, (1647-1655), Online publication date: 1-Jun-2020. Montaner J, Ramiro L, Simats A, Tiedt S, Makris K, Jickling G, Debette S, Sanchez J and Bustamante A (2020) Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke, Nature Reviews Neurology, 10.1038/s41582-020-0350-6, 16:5, (247-264), Online publication date: 1-May-2020. Takeda M, Tezuka T, Kim M, Choi J, Oichi Y, Kobayashi H, Harada K, Mizushima T, Taketani S, Koizumi A and Youssefian S (2020) Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2020.02.024, 525:3, (668-674), Online publication date: 1-May-2020. Sun X, Luo M, Li J, Lai R, Lin J, Wang Y, Xu X, Wu S and Sheng W (2020) Prevalence of RNF213 variants in symptomatic intracranial arterial stenosis/occlusion in China, Molecular Genetics and Genomics, 10.1007/s00438-020-01650-4, 295:3, (635-643), Online publication date: 1-May-2020. Geng C, Cui C, Guo Y, Wang C, Zhang J, Han W, Jin F, Chen D and Jiang P (2020) Metabolomic Profiling Revealed Potential Biomarkers in Patients With Moyamoya Disease, Frontiers in Neuroscience, 10.3389/fnins.2020.00308, 14 Kim J, Park Y, Woo M, An H, Kim J, Park H, Ryu C, Kim O and Kim N (2020) Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms, International Journal of Molecular Sciences, 10.3390/ijms21061956, 21:6, (1956) Miyawaki S and Saito N (2020) Genetic Factor for Intracranial Artery Stenosis頭蓋内血管狭窄病変の遺伝的要因, Japanese Journal of Neurosurgery, 10.7887/jcns.29.680, 29:10, (680-689), . Moussouttas M and Rybinnik I (2020) A critical appraisal of bypass surgery in moyamoya disease, Therapeutic Advances in Neurological Disorders, 10.1177/1756286420921092, 13, (175628642092109), Online publication date: 1-Jan-2020. Uemura M, Kanazawa M, Yamagishi T, Nagai T, Takahashi M, Koide S, Tada M, Shimbo J, Isami A, Makino K, Masuko M, Nikkuni K, Okamoto K, Igarashi S, Morita K and Onodera O (2020) Role of RNF213 p.4810K variant in the development of intracranial arterial disease in patients treated with nilotinib, Journal of the Neurological Sciences, 10.1016/j.jns.2019.116577, 408, (116577), Online publication date: 1-Jan-2020. Lee M, Fallen S, Zhou Y, Baxter D, Scherler K, Kuo M and Wang K (2019) The Impact of Moyamoya Disease and RNF213 Mutations on the Spectrum of Plasma Protein and MicroRNA, Journal of Clinical Medicine, 10.3390/jcm8101648, 8:10, (1648) Toyoda K, Inoue M and Koga M (2019) Small but Steady Steps in Stroke Medicine in Japan, Journal of the American Heart Association, 8:16, Online publication date: 20-Aug-2019.Kamimura T, Okazaki S, Morimoto T, Kobayashi H, Harada K, Tomita T, Higashiyama A, Yoshimoto T, Takahashi J, Nakagawara J, Koga M, Toyoda K, Maruyama H, Koizumi A and Ihara M (2019) Prevalence of RNF213 p.R4810K Variant in Early-Onset Stroke With Intracranial Arterial Stenosis, Stroke, 50:6, (1561-1563), Online publication date: 1-Jun-2019. January 8, 2019Vol 139, Issue 2 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.038439PMID: 30615506 Originally publishedJanuary 7, 2019 Keywordsstrokegenetic predisposition to diseasemoyamoya diseaseatherosclerosisRING finger domainsconstriction, pathologicPDF download Advertisement SubjectsIschemic Stroke

Referência(s)