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

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

doi:10.1161/circulationaha.118.038439

Cited by 79 publications

(68 citation statements)

References 5 publications

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“…As such, no standardization in medical therapy exists against which to compare surgical treatment, despite evidence for traditional risk factors being predictors of recurrent vascular events, 18,28,32 official guidelines recommending the use of antiplatelet agents, 1 data that vasodilators may improve perfusion in symptomatic ischemic hemispheres, 56 and evidence linking an MMD genetic susceptibility variant to the development of anterior circulation large artery atherosclerosis, in which case HMG Co-A reductase inhibitors may theoretically prove useful. 57 The frequent presence of sonographically detected microemboli also reinforces the potential importance of antiplatelet agents in preventing thromboembolic infarctions in MMD. 16,58 Of concern may be the possibility that 'conservative' treatment often implies no active medical treatment.…”

Section: Discussionmentioning

confidence: 78%

A critical appraisal of bypass surgery in moyamoya disease

Moussouttas

Rybinnik

2020

Ther Adv Neurol Disord

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Moyamoya disease (MMD) is a complex cerebrovascular disorder about which little is known. Conventionally, revascularization surgery is recommended for patients, despite an absence of conclusive data from adequate clinical trials. Underscoring the uncertainty that exists in treating MMD patients, investigators continue to present data comparing revascularization with conservative or medical management, most of which originates from East Asia where MMD is most prevalent. The purpose of this manuscript is to review contemporary large case series, randomized trials, and recent meta-analyses that compare surgical and medical treatments in adult patients with MMD, and to critically analyze the modern literature in the context of current practice standards. Data from the available literature is limited, but revascularization seems superior to conservative therapy in adult patients presenting with hemorrhage, and in preventing future hemorrhages. Conversely, evidence that surgery is superior to medical therapy is not convincing in adult patients presenting with cerebral ischemia, or for the prevention of future ischemic events. In contrast to East Asian populations, MMD in Europe and in the Americas is predominantly an ischemic disease that presents in adulthood. Adequate multinational trials are warranted.

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Section: Discussionmentioning

confidence: 78%

A critical appraisal of bypass surgery in moyamoya disease

Moussouttas

Rybinnik

2020

Ther Adv Neurol Disord

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“…Similarly, there was a study of 221 Japanese patients, which found that RNF213 4810G > A was significantly associated with anterior ICASO but not posterior ICAS [42]. In the case-control study with a total of 46,958 Japanese people, RNF213 4810G > A variant carriers more frequently had intracranial anterior circulation stenosis than non-carriers (60.0% versus 27.3%, p = 0.004) [36]. Another study of 70 early-onset stroke patients with ICASO in Japan found that 17 RNF213 4810G > A carriers had anterior ICASO, whereas only 1 carrier of this variant had posterior ICASO as well, and the RNF213 4810G > A variant was more common in patients with MCA or ACA stenosis (17/44) than in patients with posterior ICASO (1/11) [43].…”

Section: Discussionmentioning

confidence: 79%

“…In a study of 59 relatives of patients with MMD, RNF213 4810G > A heterozygous carriers had a higher risk of developing ICASO during angiographic follow-up [35]. The presence of RNF213 4810G > A variant was at increased risk for ischemic stroke, which was largely attributable to large-artery atherosclerosis [36]. Recent reports have also described associations between RNF213 variants and extracranial systemic vasculopathy involving coronary, renal, and pulmonary arteries [37][38][39].…”

Section: Discussionmentioning

confidence: 98%

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

Kim

Park

Woo

et al. 2020

IJMS

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Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14–4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11–2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

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“…The occurrence and development of MMD is multifactorial, and the underlying etiological and pathogenic mechanisms remain largely unclear (Huang et al, 2017). Most studies have focused on geographical distributions, sex predispositions, clinical manifestations, and age-specific characteristics (Okazaki et al, 2019;Sato et al, 2019). Basic research, including genomic and proteomic approaches, has been extensively conducted in the past 60 years.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic Profiling Revealed Potential Biomarkers in Patients With Moyamoya Disease

Geng

Guo

Wang³

et al. 2020

Front. Neurosci.

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Metabolomics is increasingly used to observe metabolic patterns and disease-specific metabolic biomarkers. However, serum metabolite analysis of moyamoya disease (MMD) is rarely reported. We investigated serum metabolites in MMD and compared them with those of healthy controls (HCs) using a non-targeted gas chromatographymass spectrometry (GC-MS) approach to identify metabolic biomarkers associated with MMD. Forty-one patients with MMD diagnosed by cerebral angiography and 58 HCs were recruited for our study. Comparative analyses (univariate, multivariate, correlation, heatmaps, receiver operating characteristi curves) were performed between MMD patients and HCs. Twenty-five discriminating serum metabolic biomarkers between MMD patients and HCs were identified. Compared with HCs, MMD patients had higher levels of phenol, 2-hydroxybutyric acid, L-isoleucine, L-serine, glycerol, pelargonic acid, L-methionine, myristic acid, pyroglutamic acid, palmitic acid, palmitoleic acid, stearic acid, octadecanamide, monoglyceride (MG) (16:0/0:0/0:0), and MG (0:0/18:0/0:0), and lower levels of L-alanine, L-valine, urea, succinic acid, L-phenylalanine, L-threonine, L-tyrosine, edetic acid, and oleamide. These metabolic biomarkers are involved in several pathways and are closely associated with the metabolism of amino acids, lipids, carbohydrates, and carbohydrate translation. A GC-MS-based metabolomics approach could be useful in the clinical diagnosis of MMD. The identified biomarkers may be helpful to develop an objective diagnostic method for MMD and improve our understanding of MMD pathogenesis.

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

Cited by 79 publications

References 5 publications

A critical appraisal of bypass surgery in moyamoya disease

A critical appraisal of bypass surgery in moyamoya disease

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

Metabolomic Profiling Revealed Potential Biomarkers in Patients With Moyamoya Disease

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