Moteki Yosuke, Onda Hideaki, Kasuya Hidetoshi, Yoneyama Taku, Okada Yoshikazu, Hirota Kengo, Mukawa Maki, Nariai Tadashi, Mitani Shohei, Akagawa Hiroyuki
Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (Y.M., H.O., T.Y., Y.O.).
Department of Neurosurgery, Medical Center East, Tokyo Women's Medical University, Tokyo, Japan (H.K., K.H., H.A.) Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan (H.K., K.H., S.M., H.A.).
J Am Heart Assoc. 2015 May 11;4(5):e001862. doi: 10.1161/JAHA.115.001862.
A founder variant of RNF213, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (MMD) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD.
To detect variants of RNF213, all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case-control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population-based controls. Forty-six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD. We conducted a variable threshold test using Combined Annotation-Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P=0.045).
Not only p.4810K but also other functional missense variants of RNF213 conferred susceptibility to MMD. Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF213, indicating the presence of other susceptibility genes for MMD.
RNF213的一个奠基者变异体p.R4810K（c.14429G>A，rs112735431）最近被确定为日本烟雾病（MMD）的主要遗传危险因素。尽管据报道p.R4810K的关联性非常显著且可重复，但其他RNF213变异体的疾病易感性仍基本未知。在本研究中，我们系统评估了日本患者和对照中检测到的编码变异体与MMD的关联性。
为检测RNF213的变异体，对27例无p.R4810K的日本MMD患者的所有编码外显子进行了测序。我们还在病例对照样本中验证了所有先前报道的变异体，并与先前的日本研究队列（包括千人基因组计划数据集）作为基于人群的对照进行组合检测关联性。在日本370例合并患者和279例合并对照中，除p.R4810K外还鉴定出46个错义变异体。46个变异体中有16个是次要等位基因频率>1%的多态性，在以p.R4810K基因型为条件后，与MMD无关联。我们使用联合注释依赖损耗法对其余30个罕见变异体（次要等位基因频率<1%）进行了可变阈值检验，结果显示患者中潜在功能性变异体的频率显著高于对照（置换检验，最小P=0.045）。
RNF213的不仅p.4810K而且其他功能性错义变异体也赋予了对MMD的易感性。我们的分析还显示，约20%的日本MMD患者未携带RNF213的易感性变异体，这表明存在其他MMD的易感基因。
