Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
PLoS One. 2012;7(10):e48179. doi: 10.1371/journal.pone.0048179. Epub 2012 Oct 23.
Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery causing cerebral ischemia and hemorrhage. Genetic factors in the etiology and pathogenesis of MMD are being increasingly recognized. Previous studies have shown that the RNF213 gene was related to MMD susceptibility in the Japanese population. However, there is no large scale study of the association between this gene and MMD in the Chinese Han population. Thus we designed this case-control study to validate the R4810K mutation and to define the further spectrum of RNF213 mutations in Han Chinese.
METHODOLOGY/PRINCIPAL FINDINGS: Genotyping of the R4810K mutation in the RNF213 gene was performed in 170 MMD cases and 507 controls from a Chinese Han population. The R4810K mutation was identified in 22 of 170 MMD cases (13%), including 21 heterozygotes and a single familial homozygote. Two of the 507 controls (0.4%) were heterozygous R4810K carriers. The R4810K mutation greatly increased the risk for MMD (OR = 36.7, 95% CI: 8.6156.6, P = 6.1 E-15). The allele frequency of R4810K was significantly different between patients with ischemia and hemorrhage (OR = 5.4, 95% CI: 1.816.1, P = 0.001). Genomic sequencing covering RNF213 exon 40 to exon 68 also identified eight other non-R4810K variants; P4007R, Q4367L, A4399T, T4586P, L4631V, E4950D, A5021V and M5136I. Among them A4399T polymorphism was found in 28/170 cases (16.5%) and 45/507 controls (8.9%) and was associated with MMD (OR = 2.0, 95% CI: 1.23.3, P = 0.004), especially with hemorrhage (OR = 2.8, 95% CI: 1.26.5, P = 0.014).
RNF213 mutations are associated with MMD susceptibility in Han Chinese. The ischemic type MMD is particularly related to the R4810K mutation. However, A4399T is also a susceptible variant for MMD, primarily associated with hemorrhage. Identification of novel variants in the RNF213 gene further highlights the genetic heterogeneity of MMD.
烟雾病（MMD）是一种罕见的脑血管疾病，其特征为颈内动脉逐渐闭塞导致脑缺血和出血。遗传因素在 MMD 的病因和发病机制中越来越受到重视。先前的研究表明，RNF213 基因与日本人 MMD 的易感性有关。然而，在中国汉族人群中，尚未有大规模研究该基因与 MMD 之间的关联。因此，我们设计了这项病例对照研究，以验证 RNF213 基因中的 R4810K 突变，并确定汉族人群中 RNF213 基因突变的进一步谱。
方法/主要发现：在中国汉族人群中，对 170 例 MMD 病例和 507 例对照进行了 RNF213 基因 R4810K 突变的基因分型。在 170 例 MMD 病例中发现了 22 例（13%）R4810K 突变，包括 21 例杂合子和 1 例家族性纯合子。507 例对照中有 2 例（0.4%）为 R4810K 杂合子携带者。R4810K 突变大大增加了 MMD 的发病风险（OR=36.7，95%CI：8.6156.6，P=6.1E-15）。缺血性和出血性 MMD 患者的 R4810K 等位基因频率存在显著差异（OR=5.4，95%CI：1.816.1，P=0.001）。覆盖 RNF213 外显子 40 至外显子 68 的基因组测序还鉴定了另外 8 种非 R4810K 变异体：P4007R、Q4367L、A4399T、T4586P、L4631V、E4950D、A5021V 和 M5136I。其中，A4399T 多态性在 28/170 例（16.5%）和 45/507 例对照（8.9%）中发现，并与 MMD 相关（OR=2.0，95%CI：1.23.3，P=0.004），特别是与出血相关（OR=2.8，95%CI：1.26.5，P=0.014）。
RNF213 突变与中国汉族人群的 MMD 易感性有关。缺血性 MMD 与 R4810K 突变特别相关。然而，A4399T 也是 MMD 的易感变异体，主要与出血有关。在 RNF213 基因中发现新的变异体进一步强调了 MMD 的遗传异质性。
