Dataset Information

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

ABSTRACT: Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G?>?A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P?=?1.5?×?10-28, odds ratio?=?29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.

SUBMITTER: Hongo H

PROVIDER: S-EPMC7371676 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Hongo Hiroki H Miyawaki Satoru S Imai Hideaki H Shimizu Masahiro M Yagi Shinichi S Mitsui Jun J Ishiura Hiroyuki H Yoshimura Jun J Doi Koichiro K Qu Wei W Teranishi Yu Y Okano Atsushi A Ono Hideaki H Nakatomi Hirofumi H Shimizu Tsuneo T Morishita Shinichi S Tsuji Shoji S Saito Nobuhito N

Scientific reports 20200720 1

Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants ...[more]

PMID: 32686731

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Project description: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.

Dataset Information

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Publications

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Similar Datasets

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