Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease.
Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease.
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DOI：
10.1161/jaha.115.001862
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发表时间：
2015-05-11
影响因子：
5.4
通讯作者：
Akagawa H
中科院分区：
文献类型：
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作者：
Moteki Y;Onda H;Kasuya H;Yoneyama T;Okada Y;Hirota K;Mukawa M;Nariai T;Mitani S;Akagawa H
RNF213基因的一个奠基者变异体p.R4810K（c.14429G>A，rs112735431）最近被鉴定为日本烟雾病（moyamoya disease，MMD）的一个主要遗传危险因子。尽管据报道p.R4810K的关联是高度显著和可重复的，但其他RNF213变体的疾病易感性在很大程度上仍然未知。在本研究中，我们系统地评估了在日本患者和对照组中检测到的编码变异与MMD的相关性。为了检测RNF213的变异体，对27名日本MMD患者的所有编码外显子进行测序，这些患者没有p.R4810K。我们还验证了我们病例对照样本中所有先前报告的变异，并结合先前的日本研究队列（包括1000个基因组项目数据集）作为基于人群的对照进行了相关性测试。在日本的370名合并患者和279名合并对照中，确定了46种p.R4810K以外的错义变异。46个变异体中有16个是次要等位基因频率> 1%的多态性，并且在p.R4810K基因型调节后，与MMD无关。我们使用联合注释依赖性耗竭对其余30种罕见变异（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的频率显著高于对照组（排列，最小P=0.045）。不仅p.4810K，而且RNF213的其他功能性错义变体赋予MMD易感性。我们的分析还显示，约20%的日本MMD患者没有携带RNF213的易感性变体，表明存在MMD的其他易感基因。
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.