Department of Epidemiology and Health Statistics, XiangYa School of Public Health, Central South University, Shang Mayuanling, KaiFu District, Changsha, 410078, China.
Department of Neurology, the Second Hospital of Hebei Medical University, Heping West Road, Xinhua District, Shijiazhuang, 050000, China.
Environ Health Prev Med. 2017 Nov 2;22(1):75. doi: 10.1186/s12199-017-0680-1.
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.
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.
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.
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.
最近有研究表明，环指蛋白 213 基因（RNF213）的 p.R4810K 及其他罕见变异是烟雾病（MMD）和非烟雾病颅内动脉狭窄/闭塞性疾病（ICASO）的易感变异。然而，即使在同一人群的研究中，p.R4810K 的效应大小也存在很大差异，而且由于样本量小且缺乏复制，其他罕见变异的结论也难以确定。因此，我们进行了这项研究，以定量评估 RNF213 的罕见变异是否以及在何种程度上导致不同人群发生 MMD 和 ICASO。
系统检索 PubMed、EMBASE、ISI 网络科学、中国知网（CNKI）和万方数据，检索时间截至 2017 年 9 月 5 日。采用随机或固定效应模型，根据研究间的异质性，计算合并的比值比（OR）及其 95%置信区间（CI）。根据种族和家族史进行亚组分析。采用敏感性和发表偏倚分析来检验关联的稳健性。所有统计分析均采用 STATA 12.0 进行。
本研究共纳入 20 项研究，包括 2353 例 MMD 病例和 5488 例对照，以及 11 项研究，包括 1778 例 ICASO 病例和 3140 例对照。汇总 OR 表明，RNF213 p.R4810K 显著增加了东亚人群 MMD 和 ICASO 的发病风险，且差异的效应大小很大（显性模型：日本、韩国和中国的 MMD 和 ICASO 的 OR 分别为 184.04、109.77 和 31.53 以及 10.07、28.52 和 5.59）。该变异还显著增加了日本、韩国和中国的家族性 MMD 发病风险，其效应大小分别是各自散发性病例的 536 倍（显性模型 OR 分别为 1802.44、512.42、1109.02 和 134.35、99.82 和 30.52）。与中国相比，日本和韩国的 RNF213 p.R4810K 对散发性 MMD 的效应大小分别为 34 倍。RNF213 p.R4810K 还增加了日本和韩国的 ICASO 发病风险，其效应大小分别是中国的 2~4 倍（显性模型 OR 分别为 10.71、28.52 和 5.59）。另外两个罕见变异 p.E4950D 和 p.A5021V 也显著增加了中国人群的 MMD 发病风险（显性模型 OR 分别为 9.06 和 5.01）。在日本、中国、欧洲和西班牙裔美国人人群中还发现了其他一些 RNF213 的罕见变异，但目前还没有关联证据。
本荟萃分析表明，RNF213 p.R4810K 在日本、韩国和中国的 MMD 特别是家族性 MMD 和 ICASO 中起关键作用。除了 RNF213 p.R4810K 之外，MMD 在中国似乎还有更复杂的决定因素。存在不同的遗传背景，其他环境或遗传因素可能导致 MMD。需要进一步研究以明确 RNF213 变异在 MMD 和 ICASO 中的种族特异性因素和病理作用。
