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

Abstract

Background: The 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.

Methods: A 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.

Results: Twenty 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.

Conclusions: This 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.

Keywords: Genetics; Intracranial stenosis disease; Moyamoya disease; RNF213, rare variants; Review.

Fig. 1

PRISMA flow diagram of study selection process

Fig. 2

Forest plots for the association of RNF213 p.R4810K with MMD under the dominant model. a Forest plots of RNF213 p.R4810K and sporadic MMD in different subgroup populations under the dominant model. b Forest plots of RNF213 p.R4810K and familial MMD in different subgroup populations under the dominant model

Fig. 3

Forest plots for the association of RNF213 p.E4950D and p.A5021V with MMD under the dominant model. a Forest plots of RNF213 p.E4950D and MMD in Chinese population under the dominant model. b Forest plots of RNF213 p.A5021V and MMD in Chinese population under the dominant model

Fig. 4

Forest plots for the association of RNF213 p.R4810K with ICASO under the dominant model. a Forest plots of RNF213 p.R4810K and ICASO in the general population under the dominant model. b Forest plots of RNF213 p.R4810K and ICASO in the subgroup populations under the dominant model

Fig. 5

Funnel plots for the association of RNF213 p.R4810K with MMD and ICASO under the dominant model. a Funnel plot of RNF213 p.R4810K and MMD under the dominant model. b Funnel plot of RNF213 p.R4810K and ICASO under the dominant model

Fig. 6

Other rare variants of RNF213 identified in MMD individuals. The figure was adapted from Cecchi et al. [14] and Koizumi et al. [29]. Variants identified in different populations are marked in different colors respectively. AA, amino acid; AAA+, ATPase associated with diverse cellular activities domain. The bold-styled variant mean the most robust one associated with MMD