Rare variants of RNF213 and moyamoya/non-moyamoya intracranial artery stenosis/occlusion disease risk: a meta-analysis and systematic review

Abstract

BackgroundThe p.R4810K and other rare variants of ring finger protein 213 gene (RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non-moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations.MethodsA systematic search of PubMed, EMBASE, ISI web of science, CNKI, and WANFANG DATA was conducted up to 5 September 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0.ResultsTwenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy (dominant model: odds ratios 184.04, 109.77, and 31.53 and 10.07, 28.52, and 5.59 for MMD and ICASO, respectively, in Japan, Korea, and China). It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country (dominant model ORs 1802.44, 512.42, 1109.02 and 134.35, 99.82, and 30.52, respectively, for familial and sporadic cases). The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China (dominant model ORs 10.71, 28.52, and 5.59, respectively). Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population (dominant model ORs 9.06 and 5.01, respectively). Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet.ConclusionsThis meta-analysis shows the critical roles of RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.Electronic supplementary materialThe online version of this article (10.1186/s12199-017-0680-1) contains supplementary material, which is available...

Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

“…11 The RNF213 c.14429G>A (p.Arg4810Lys, rs112735431) variant is a founder mutation and found as the risk allele for Moyamoya disease in the East Asian population, with a high odds ratio. 11,12 Intriguingly, the penetrance of this specific founder mutation must be low, but if disease phenotypes based on this mutation appear, vascular diseases in several organs, at least in the brain and lung, are induced. 5,6 We previously reported one family with the RNF213 p.Arg4810Lys variant in which the mother developed PAH (Case #4), and her daughter exhibited Moyamoya disease, 3 suggesting the presence of RNF213-associated vascular diseases.…”

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

“…Beyond the association with MMD, a number of studies have reported frequent RNF213 variants in patients with non-MMD ICASO [2,31,32]. In a meta-analysis of 11 studies including 1778 ICASO patients and 3140 controls in East Asians, RNF213 4810G > A was significantly associated with an increased risk of ICASO [17]. High-resolution magnetic resonance angiography (MRA) showed that ICASO with RNF213 4810G > A was associated with a negative remodeling pattern, which is a hallmark of MMD, in contrast to the positive remodeling pattern of classical atherosclerotic ICASO [33].…”

“…The RNF213 gene encodes a RING finger protein that possesses both ubiquitin ligase activity and ATPases associated with diverse cellular activities' (AAA+) ATPase activity [16]. Although RNF213 variants have been associated with various vascular disorders, the mechanisms through which they contribute to these disorders are unknown [17]. Experimental reports have suggested multiple pathogenic mechanisms involving endothelial function, smooth muscle cell proliferation, inflammatory signaling pathways, hemostasis, angiogenesis, vascular remodeling, and response to hypoxia [7,9,10,[18][19][20][21][22].…”

“…We adjusted for multiple conventional vascular risk factors, but the possibility of unknown potential confounding factors remains. Although we excluded MMD patients based on angiographic findings, it is possible that patients with early changes or atypical patterns of MMD might have been included, which may have contributed to the association between ICASO and RNF213 variants [17,31,33]. In addition, the study was performed at a single hospital, and a large portion of the study participants had ischemic stroke.…”

PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause

“…Constitutional hotspot variants in RNF213 have been reported in a variety of subsequent studies (Hitomi et al, ; Liu et al, ; Ma et al, ; Roder et al, ). The RNF213 mutation p.R4810K was confirmed to be associated with familial MMD risk in Japan, Korea, and China in a meta‐analysis and systematic review (Liao, Deng, Dai, Zhang, & Yan, ). Several patients with PHACE syndrome and MMV have been reported (Jack et al, ; Sathishkumar, George, Irodi, & Thomas, ; Schilter et al, ; Tortora et al, ).…”