Moyamoya disease in Southeast Asians: genetic and autopsy data, new cases, systematic review, and meta-analysis of all patients from the literature.

BACKGROUND: Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans. METHODS: By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination. RESULTS: The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case. CONCLUSION: Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.

Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia.

Background: The RNF213 p.R4810K variant is associated with moyamoya disease in East Asian individuals and increases the risk of developing intracranial major artery stenosis/occlusion (ICASO) that affects anterior circulation. Meanwhile, 0.5% to 2.5% of asymptomatic East Asian individuals also carry this variant. As such, additional factors are likely required to develop ICASO in variant carriers. Familial hypercholesterolemia (FH) is a common genetic disorder in Japan that has a significant associated risk of developing premature coronary atherosclerosis; however, the relationship between ICASO and FH remains unknown. Objectives: This study aimed to determine if FH facilitates RNF213 p.R4810K carriers to develop ICASO. Methods: We enrolled patients with FH who had undergone brain magnetic resonance angiography at our hospital from May 2005 to March 2020. The RNF213 p.R4810K variant, and LDLR and PCSK9 mutations were genotyped. ICASO lesions in the brain magnetic resonance angiogram were analyzed. Results: Six RNF213 p.R4810K variant carriers were identified among 167 patients with FH (LDLR, n = 104; PCSK9, n = 22). Five of the carriers (83.3%) exhibited ICASO in the anterior circulation; a significant difference in ICASO frequency was observed between the variant carriers and noncarriers (P = 0.025). The median number of stenotic or occluded arteries in the anterior circulation was also significantly larger in the variant carriers (3 vs 1, P = 0.01); however, did not differ between patients with FH with LDLR and PCSK9 mutations. Conclusions: Patients with FH exhibit increased prevalence and severity of ICASO associated with RNF213 p.R4810K. Gene mutations for FH may confer an increased risk of ICASO in RNF213 p.R4810K carriers.

A long-term study of posterior circulation changes after revascularization in patients with moyamoya disease.

OBJECTIVE: This study aimed to explore the long-term course of posterior circulation changes and predictors in patients with moyamoya disease (MMD). METHODS: The authors retrospectively enrolled patients who were diagnosed with MMD and underwent encephaloduroarteriosynangiosis (EDAS) surgery at the authors' department from December 2002 to September 2011. A comparative study between short-term (6-12 months) and long-term (≥ 9 years) follow-up angiography was conducted. The progression of lesions was defined from lower to higher stages of the posterior cerebral artery (PCA). RESULTS: Eighty-eight patients who received indirect EDAS were enrolled in the study. The mean age at first surgery was 28.1 ± 15.0 years. Among these 88 patients with MMD, 39 (44.3%) exhibited transient ischemic attack and 27 (30.7%) exhibited infarction, comprising 5 with occipital lobe infarction, 14 (15.9%) with hemorrhagic symptoms, and 8 (9.1%) with atypical symptoms as the initial symptoms. Heterozygous mutations occurred significantly more frequently in the cases that presented with PCA involvement. During follow-up, stage progression of PCA was observed in 21 patients (28 hemispheres). At short-term follow-up, 21/176 (11.9%) hemispheres had progression of steno-occlusive lesions in the PCA. At long-term follow-up, 7 (4.0%) hemispheres had progression of steno-occlusive lesions in the PCA. At short-term follow-up, the progression of steno-occlusive lesions in the PCA was associated with progression of the internal carotid artery. Stage progression of PCA occurred significantly more frequently in the cases with PCA involvement on preoperative angiography. Nine strokes (10.2%) occurred in 88 patients during long-term follow-up. Four patients (4.5%) presented with ischemic stroke, including 2 with occipital lobe infarctions. CONCLUSIONS: Progression of PCA stenosis is common in patients with MMD, even if the PCA is normal initially. Mutations of RNF213 p.R4810K may predict PCA involvement or progression. Follow-up of the PCA in MMD patients should be conducted, and timely surgical revascularization is needed.

The Potential Mechanism Behind Native and Therapeutic Collaterals in Moyamoya.

Background and Purpose: To explore the genetic basis and molecular mechanism of native arteriogenesis and therapeutic synangiosis in moyamoya disease (MMD). Methods: An angiography-based study using patients from a prospective trial of encephaloduroarteriosynangiosis (EDAS) surgery was performed. The spontaneous collaterals grades were evaluated according to the system described by a new grading system. Blood samples were collected from all the recruited patients before EDAS and during the second hospitalization 3 months post-EDAS. We performed Boolean analysis using a combination of specific cell surface markers of CD34briCD133+CD45dimKDR+. Genotyping of p.R4810K was also performed. The correlation of age, sex, initial symptoms at diagnosis, collateral grade, Suzuki stages, the RNF213 genotype, time to peak (TTP), and endothelial progenitor cell (EPC) count with good collateral circulation was evaluated. Results: Eighty-five patients with MMD were included in this study. The mutation rate of RNF213 p.R4810K in our study was 25.9% (22/85). The heterozygous mutations were occurred significantly more frequently in the cases that were presented with infarction, worse neurological status, severe posterior cerebral artery (PCA) stenosis, and longer TTP delay. Further, the heterozygous mutations occurred significantly more frequently in the poor collateral stage group. Lower grades were significantly correlated with severe ischemia symptoms, worse neurological status, and a longer TTP delay. The post-operative angiographic findings showed that a good Matsushima grade was correlated with heterozygous mutations, a lower collateral stage, and a longer TTP delay. The CD34briCD133+CD45dimKDR+ cell count in patients 3 months post-EDAS was significantly higher as compared to the count before EDAS in the good Matsushima grade group. However, this change was not observed in the poor Matsushima grade group. Conclusions: These data imply that mutations of RNF213 p.R4810K affect the establishment of spontaneous collateral circulation, and EPCs are involved in the process of formation of new EDAS collaterals.

Validation and Extension Study Exploring the Role of RNF213 p.R4810K in 2,877 Chinese Moyamoya Disease Patients.

OBJECTIVE: To validate, update, and extend the role of RNF213 p.R4810K (G>A) for predicting the phenotype of moyamoya disease (MMD) patients and explore the different effects on pediatric and adult groups. METHODS: A total of 2,877 patients conducted from 2004 to 2018 were included. Review Manage 5.3 and SPSS 20.0 were applied to complete all statistical analyses. Information on age at onset, sex, initial symptom, family history and complications were obtained via retrospective chart review. Angiographic records were evaluated. RESULTS: In China, geographic proximity to Korea or Japan may affect the carrying rate of RNF213 p.R4810K. The proportion of patients with the following characteristics was significantly higher (P <0.017) in the GA than in the GG group: female, age at onset < 18 years, infarct after transient ischemic attack, family history of MMD, and posterior cerebral artery involvement. For pediatric patients, GA showed more cerebral hemorrhage (CH) (odds ratios (ORs) [95% confidence intervals (CIs)] = 3.99 (1.61-9.88), P = 0.003), more patients were in the Suzuki early and intermediate stage (P = 0.001; P = 0.001, respectively), while for the adult group, GA indicated more female (OR [95% CIs] = 1.43 [1.15-1.79], P = 0.001), fewer patients with diabetes (0.58 [0.38-0.86], P = 0.007) and intermediate Suzuki stage (P = 3.70 × 10-4). CONCLUSIONS: The incidence and carrying rates of RNF213 p.R4810K in various regions for Chinese MMD patients were obviously different. RNF213 p.R4810K has different predictive effects on phenotypes of pediatric and adult patients.

RNF213 p.R4810K (c.14429G > A) Variant Determines Anatomical Variations of the Circle of Willis in Cerebrovascular Disease.

INTRODUCTION: Dysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease. PATIENTS AND METHODS: The present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded. RESULTS: Four hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant. CONCLUSION: Our findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.

Meta-analysis of genotype and phenotype studies to confirm the predictive role of the RNF213 p.R4810K variant for moyamoya disease.

BACKGROUND AND PURPOSE: The aim of this meta-analysis study was to assess the predictive effects of RNF213 p.R4810K on phenotype in moyamoya disease (MMD). METHODS: Electronic databases (e.g., Pubmed and EMBASE) were searched, and relevant articles published up to August 2020 were retrieved. Review Manager 5.3 and Stata 12.0 were used for all statistical analyses. Pooled odds ratios, with 95% confidence intervals, and three comparison models were evaluated to analyze the association between RNF213 pR4810K variant and clinical characteristics of MMD patients using a fixed-effects model. RESULTS: A total of 2798 patients with MMD were selected and the effects of the heterozygous or homozygous RNF213 p.R4810K variant on 18 clinical features were identified. There were more patients aged <15 years in the GA and AA groups (AA vs GA: p = 0.009; AA vs GG: p = 0.003; GA vs GG: p = 0.001). Among homozygous patients, the majority experienced MMD onset before the age of 4 years (AA vs. GA: p < 0.00001; AA vs GG: p < 0.00001). The frequency of infarctions and transient ischemic attack was significantly higher in homozygotes and heterozygotes，respectively. However, the frequency of intracerebral/intraventricular hemorrhage was lower in patients with the GA than the GG genotype. More MMD patients with AA and GA genotypes had a family history of the disease (p = 0.003, p < 0.00001, respectively). Posterior cerebral artery involvement was more common in patients with the GA genotype (p < 0.00001). CONCLUSION: The homozygous or heterozygous RNF213 variant may be an efficient biomarker with which to classify different clinical phenotypes of MMD.

Observation of p.R4810K, a Polymorphism of the Mysterin Gene, the Susceptibility Gene for Moyamoya Disease, in Two Female Japanese Diabetic Patients with Familial Partial Lipodystrophy 1.

Mysterin, which was recently shown to play an important role in maintaining cellular fat storage, has been identified to be the susceptibility gene for moyamoya disease (MMD). We encountered some female Japanese patients with partial lipodystrophy and MMD-like vascular lesions. This prompted us to examine whether mysterin variants may be present in these patients. We identified a mysterin variant, p.R4810K in two patients with MMD-like vascular lesions, who may fit the category of familial partial lipodystrophy (FPLD) 1. Our cases suggest the possibility that p.R4810K, in addition to atherogenic risk factors, might thus play a role in the development of atherosclerotic lesions in patients with FPLD1 and p.R4810K.

Different subtypes of collateral vessels in hemorrhagic moyamoya disease with p.R4810K variant.

BACKGROUND: The aim of this study was to investigate the hemorrhgic sites and collateral vessels in hemorrhagic MMD with the p.R4810K variant. METHODS: Hemorrhage sites were classified as either anterior or posterior. Collateral vessels were classified into three subtypes according to origin: lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis. Hemorrhage sites and collateral vessels were compared between patients with wild-type p.R4810K variant (GG) and patients with heterozygous p.R4810K variant (GA) after 1:1 propensity score matching. RESULTS: A total of 130 hemorrhagic MMD patients were included in present study, 21 pairs (42 hemorrhagic hemispheres) were obtained after 1:1 propensity score. In GA group, 16 hemispheres (76.2%) presented anterior hemorrhage, and 5 hemispheres (23.8%) presented with posterior hemorrhage. In GG group, 13 hemispheres (61.9%) presented anterior hemorrhage, and 8 hemispheres (38.1%) presented with posterior hemorrhage. No significant differences were found in hemorrhagic sites between two matched groups (P > 0.05). Of 21 hemispheres in GA group, 10 (47.6%) exhibited lenticulostriate anastomosis, 6 (28.6%) thalamic anastomosis, and 6 (28.6%) choroidal anastomosis. Of 21 hemispheres in GG group, 3 (14.3%) exhibited lenticulostriate anastomosis, 5 (23.8%) thalamic anastomosis, and 9 (42.9%) choroidal anastomosis. There was significant difference in lenticulostriate anastomosis between two matched groups (P = 0.045). After adjustment the age, sex, and PCA involvement, we found that lenticulostriate anastomosis was associated with p.R4810K variant (OR, 5.995; 95% CI, 1.296-27.737; P = 0.022). CONCLUSION: Lenticulostriate anastomosis might be associated with p.R4810K variant. Whereas hemorrhagic sites, thalamic anastomosis, and choroidal anastomosis might not be associted withp.R4810K variant.

Angiographic characteristics in Moyamoya disease with the p.R4810K variant: a propensity score-matched analysis.

BACKGROUND AND PURPOSE: The p.R4810K variant was identified as a strong susceptibility in patients with Moyamoya disease (MMD). The aim of this study was to investigate the angiographic characteristics in MMD with the p.R4810K variant. METHODS: Angiographic characteristics were compared between patients with wild-type p.R4810K variant (GG) and patients with heterozygous p.R4810K variant (GA) after 1:1 propensity score matching, including Suzuki stage, collateral circulation and external carotid artery (ECA) collateral. Collateral circulation was graded with scores ranging from 0 to 12: posterior collateral circulation from the posterior cerebral artery to the middle cerebral artery and anterior cerebral artery was scored from 0 to 6; anterior collateral circulation was scored as 6 to 0 corresponding to Suzuki stages 0 to 6. RESULTS: A total of 489 patients were screened; 133 pairs were obtained after 1:1 propensity score matching. Compared with the patients in the GA group, unilateral MMD was more frequent in the GG group (P = 0.026). Hemispheres in the GA group (86/266) had more posterior cerebral artery involvement than hemispheres in the GG group (48/266) (P < 0.001). Hemispheres in the GA group had a lower grade in collateral circulation than hemispheres in the GG group (P = 0.011), but ECA collateral was more frequently observed in the GA group than in the GG group (53.4% vs. 39.8%, P = 0.002). Superficial temporal artery and occipital artery collateral was more frequently observed in the GA group than in the GG group (P < 0.05). CONCLUSIONS: Patients in the GA group had lower grades in collateral circulation than patients in the GG group, but ECA collateral was more frequently observed in the GA group than in the GG group.

Association between p.R4810K Variant and Postoperative Collateral Formation in Patients with Moyamoya Disease.

OBJECT: To investigate the association between p.R4810K variant and postoperative collateral formation (PCF) in patients with moyamoya disease. METHODS: The p.R4810K variant was detected in 254 Chinese moyamoya patients. Surgically treated 273 hemispheres with preoperative and postoperative digital subtraction angiography were included. PCF was evaluated on lateral and anteroposterior views using angiography. Univariate and multivariate logistic regression analyses were performed to determine the influence factors for PCF. RESULTS: Among 254 patients, 191 (75.2%) patients carried wild-type p.R4810K variant (GG) and 63 patients (24.8%) carried the heterozygous p.R4810K variant (GA). PCF was better in patients with GA than in patients with GG both on lateral views and anteroposterior views (p < 0.001 and p < 0.001). Over the median 7 months follow-up after discharge, good PCF was observed in 201 hemispheres (73.6%), and poor PCF was observed in 72 hemispheres (26.4%). The univariable logistic regression showed that patients with GA (OR 4.681; 95% CI 1.925-11.383; p = 0.001) was associated with good PCF. On the other hand, the increasing age (OR 0.971; 95% CI 0.952-0.989; p = 0.002) and the presence of hemorrhage (OR 0.189; 95% CI 0.096-0.374; p = 0.000) were associated with poor PCF. Multivariate logistic regression analyses of p.R4810K variant and clinical variables showed that GA (OR 3.671; 95% CI 1.452-9.283; p = 0.006) was associated with a good PCF, while the presence of hemorrhage (OR 0.258; 95% CI 0.065-0.362; p = 0.000) was identified as a predictor of poor PCF. CONCLUSIONS: The heterozygous p.R4810K variant was associated with better PCF.

Association Between p.R4810K Variant and Long-Term Clinical Outcome in Patients With Moyamoya Disease.

Objective: To estimate the association between p. R4810K variant and clinical outcomes of patients with moyamoya disease (MMD). Methods: The p.R4810K genetic variant was genotyped among 498 Chinese patients with MMD conducted from June 1, 2012, to June 31, 2017. Data was obtained by retrospective chart review, follow-up information and outcome were obtained through clinical visits and telephone. Results: Among 498 patients, 361 (72.5%) were wild-type patients (G/G), 133 (26.7%) heterozygous patients (G/A), and 4 (0.8%) homozygotes (A/A). Compared with GG group, the patients in the G/A+A/A group were younger at diagnosis and had more familial cases, more transient ischemic attack cases, more posterior cerebral artery involved hemispheres, less unilateral lesions. After the median 53 months follow-up, strokes occurred in 9 patients in the G/A+A/A group and in 52 in the G/G group. Multivariate Cox regression analysis showed that the history of hypertension (HR, 2.294; 95% CI, 1.251-4.206; p = 0.007), the presence of TIA (HR, 0.319; 95% CI, 0.120-0.846; p = 0.022), and the Suzuki stage (HR, 1.510; 95% CI, 1.129-2.018; p = 0.005) were associated with recurrent stroke. The p.R4810K (HR, 0.601; 95% CI, 0.292-1.239; p = 0.168) was not associated with recurrent stroke. Multivariate logistic regression analysis showed that recurrent stroke (OR, 5.997; 95% CI, 2.583-13.924; p = 0.000) was the only factor associated with unfavorable neurological status. And the p.R4810K (OR, 0.885; 95% CI, 0.482-1.627; p = 0.695) was not associated with neurological status. Conclusions: Compared to the patients in G/G group, patients in G/A+A/A group exhibited different clinical features, and had a lower rate of recurrent stroke and better clinical outcome after early medical and surgical interventions. Multivariate COX and logistic regression analysis showed that p.R4810Kvariant was not related to either recurrent stroke or neurological status. The p.R4810Kvariant may not be associated with long-term clinical outcome in Chinese patients with MMD.

Recent advance in association between ring finger protein 213 gene p.R4810K and moyamoya disease / 中华神经医学杂志

Moyamoya disease (MMD) is a chronic progressive steno-occlusive vasculopathy that involves terminal portions of the bilateral internal carotid arteries and/or the initial segment of the middle cerebral arteries and/or the initial segment of the anterior cerebral arteries. Ring finger protein 213 gene (RNF213) is considered as the major susceptibility gene of MMD.RNF213p.R4810K is mainly distributed in East Asians and is the founder variant of Asian patients with MMD.RNF213p.R4810K is associated with the incidence, prevalence, severity of illness and clinical manifestations of MMD. The biochemical mechanisms ofRNF213p.R4810K are still unclear and may affect angiogenesis of endothelial cells through both cell cycle-dependent and cell cycle-independent mechanisms. This paper reviews the research progress ofRNF213p.R4810K and the related mechanisms in MMD.

RNF213 p.R4810K Polymorphism and the Risk of Moyamoya Disease, Intracranial Major Artery Stenosis/Occlusion, and Quasi-Moyamoya Disease: A Meta-Analysis.

BACKGROUND: Accumulating studies have reported that there is an association between the Ring finger protein 213 (RNF213) p.R4810K (rs112735431, c.14576G>A) single nucleotide polymorphism and the predisposition of moyamoya disease (MMD), intracranial major artery stenosis/occlusion (ICASO), quasi-moyamoya disease (quasi-MMD), and other vascular diseases. However, to this day, analyses about this association have remained scarce in the literature. We attempted to conduct a meta-analysis to systematically summarize and clarify the issue. METHODS: Electronic databases dated up to January 2018 were searched, retrieved, and used. Revman 5.2 software and STATA version 12.0 were used for statistical analysis. The association between RNF213 p.R4810K and MMD, ICASO, and quasi-MMD were assessed by odds ratios and 95% confidence intervals using fixed effects models. Between-study heterogeneity was evaluated by I-squared (I2) statistics and sensitivity analysis was performed by omitting 1 study at a time. A funnel plot and Begg's test were used to assess the potential publication bias. RESULTS: The outcomes showed a statistically significant association between RNF213 p.R4810K and MMD, ICASO, and quasi-MMD, especially in the dominant model. Apart from the first 2 diseases, no significant association was identified under the recessive, the homozygote, and the heterozygote models in ICASO. CONCLUSIONS: RNF213 p.R4810K was associated with MMD, ICASO, and quasi-MMD in different genetic models. Subgroup analysis indicated highly significantly higher risk in the Japanese patients. However, further well-designed studies with larger sample size and comprehensive data are needed to confirm our findings and provide a profound conclusion.

Development of atherosclerotic-moyamoya syndrome with genetic variant of RNF213 p.R4810K and p.T1727M: A case report.

OBJECTIVE: We report a rare case of atherosclerotic-moyamoya syndrome (A-MMS) in an adult female with genetic variant of both ring finger 213 (RNF213) p.R4810K and p.T1727M. CASE REPORT: A 46-year-old previously healthy, right-handed woman displayed transient slurred speech, which started to worsen four years ago. Initial magnetic resonance angiography (MRA) revealed stenosis in left middle cerebral artery (MCA), bilateral anterior cerebral artery (ACA), and left posterior cerebral artery (PCA). The patient subsequently underwent catheter angiography, which confirmed the formation of moyamoya vessels, with Suzuki's angiographic staging of grade-3 on the left side. Although the patient had been on both anti-platelet and statin therapy at the time, a follow-up examination showed further exacerbation of left MCA stenosis, along with enhanced moyamoya vessel formation. On black-blood imaging using DANTE-SPACE, there were eccentric, evolving lesions in the left MCA. We next screened for potential genetic variants, using genomic DNA samples isolated from both the patient and her immediate family members. The results showed that the patient, along with her mother, sister, and brother, possessed the heterozygous variant of the RNF213 gene, including c.14429G > A (p.R4810K) and c.5180C > T (p.T1727M). The patient's daughter did not have the variant. CONCLUSION: Collectively, we present a unique case of A-MMS with genetic variant of RNF213 p.R4810K and p.T1727M, manifesting as progression. Based on the family tree, these two mutations are on the same RNF213 haplotype. Whether atherosclerosis is the cause of A-MMS or it further exacerbates the injury of MMD to the A-MMS patients with RNF213 gene variant is a question to be investigated.

Association of Ring Finger Protein 213 Gene P.R4810k Polymorphism with Intracranial Major Artery Stenosis/Occlusion.

BACKGROUND: Intracranial major artery stenosis/occlusion (ICASO) is a common cause of ischemic stroke worldwide. A number of studies have assessed the association of the p.R4810K polymorphism in the ring finger protein 213 (RNF213) gene with ICASO, but the results have not been entirely consistent. METHODS: We conducted a case-control study to estimate the association between the p.R4810K polymorphism and the risk of ICASO in a Chinese population. A total of 124 patients and 230 controls were enrolled. Moreover, a meta-analysis was performed to evaluate this association in the East Asian populations. RESULTS: In our case-control study, the frequencies of the G/A genotype of p.R4810K were significantly higher in the ICASO patients than in the control group (4.03% versus .43%, P = .021, respectively). Moreover, in the meta-analysis, we assessed 7 case-control studies that included 1239 patients and 1377 controls. The pooled odds ratios (ORs) indicated significant association between the p.R4810K polymorphism and the ICASO risk in the dominant model (OR = 9.37, 95% confidence interval: 4.61-19.02, P = .000), the heterozygote comparison (OR = 8.97, 95% CI: 4.41-18.25, P = .000), and the allele comparison (OR = 9.50, 95% confidence interval: 4.71-19.19, P = .000) in the East Asian populations. Subgroup analysis based on ethnicity revealed that the risks in the Japanese and the Korean populations were higher than that in the Chinese population. CONCLUSIONS: The p.R4810K polymorphism was associated with an increased risk of ICASO in the East Asian populations. Further studies on the function of the RNF213 protein and the clinical features of this subtype of ICASO are needed.

Genetic analysis of RNF213 p.R4810K variant in non-moyamoya intracranial artery stenosis/occlusion disease in a Chinese population.

OBJECTIVES: RNF213 p.R4810K was identified as a susceptibility variant for moyamoya disease in Asia and non-moyamoya intracranial artery stenosis/occlusion disease in Japan and Korea recently. The occurrence of this variant was evaluated in patients with non-moyamoya intracranial artery stenosis/occlusion disease in China. METHODS: Two study populations were used in this study. One was recruited from the Second Hospital of Hebei Medical University from April 2015 to May 2016. The other was the archived DNA samples of intracranial artery stenosis/occlusion patients in XiangYa Hospital collected in 2014. The occurrence of RNF213 p.R4810K was investigated in a total of 715 patients with non-moyamoya intracranial artery stenosis/occlusion disease. The carrier rate of RNF213 p.R4810K in 507 normal individuals was used as control. RESULTS: Six of 715 patients (0.84%) with non-moyamoya intracranial artery stenosis/occlusion disease and 2 of the 507 normal controls (0.39%) had RNF213 p.R4810K variant. The carrier rate of RNF213 p.R4810K was higher in non-moyamoya intracranial artery stenosis/occlusion group than that in the normal group. However, no statistically significant association was observed (Odds ratio, 2.14; 95% confidence interval, 0.43-10.63; p = 0.56). CONCLUSIONS: The carrier rate of RNF213 p.R4810K in Chinese non-moyamoya intracranial artery stenosis/occlusion disease patients was significantly lower than that in Korea or Japan. Genetic heterogeneity was highly indicated. Further systematic genetic epidemiology studies with emphasis on Chinese-specific genetic variants and environmental risk factors of intracranial artery stenosis/occlusion disease in larger population are needed.

Differences in the Genotype Frequency of the RNF213 Variant in Patients with Familial Moyamoya Disease in Kyushu, Japan.

The p.R4810K (rs11273543, c.14429G > A) variant of the RNF213 gene is associated with increased risk of Moyamoya disease (MMD), which is an idiopathic progressive intracranial vascular steno-occlusive disease, in Asian populations. Numerous variant association studies for this MMD variant have been performed in Japan to date. Since another genetic study that utilized approximately 140,000 single nucleotide polymor (SNPs) has indicated that there still are genetic differences among mainland Japanese, there is a possibility that the variant distribution in patients with MMD and normal individuals varies between different Japanese regions. Additionally, the majority of variant association studies have used Sanger sequencing, which is labor-intensive, time-consuming, and costly. In this study, we analyzed the frequency of the variant genotype in patients with MMD and normal individuals in Kyushu using pyrosequencing, which is an accurate, cost-effective, and automated method. We found differences in the genotype frequencies in familial patients from Kyushu and normal populations in Tohoku compared with west Japan, which suggested that there were differences in the frequency of the variant among different regions in Japan.