Molecular Analysis of RNF213 Gene for Moyamoya Disease in the Chinese Han Population

Abstract

BackgroundMoyamoya 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 FindingsGenotyping 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: 8.6∼156.6, P = 6.1 E-15). The allele frequency of R4810K was significantly different between patients with ischemia and hemorrhage (OR = 5.4, 95% CI: 1.8∼16.1, 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: 1.2∼3.3, P = 0.004), especially with hemorrhage (OR = 2.8, 95% CI: 1.2∼6.5, P = 0.014).Conclusions 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.

Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease

“…18 In the present study, patients with a family history of MMD were more likely to carry the c.14429G>A allele than those with no family history. This finding supported previous research 18,28 that showed c.14429G>A (p.R4810K) to be one of the main genetic mutations associated with familial MMD.…”

“…21 In addition, a study involving Chinese patients documented an association between the c.14429G>A (p.R4810K) allele and the ischemic-type MMD and an association between g.115456G>A (p.A4399T) and the hemorrhagic-type MMD. 28 These results corresponded with our findings that homozygous c.14429G>A (p.R4810K) was significantly associated with a young age at disease onset, cerebral infarction at presentation, and poor cognitive outcomes.…”

“…7,17,18,21,28 This study is the first to evaluate an association between the RNF213 polymorphism and the phenotype of MMD in Korean patients. With the exception of a novel variant in 1 patient, the only variant identified in our cohort of 165 patients was c.14429G>A (p.R4810K).…”

“…7,17,18,21,28 Several single nucleotide polymorphisms (SNPs) in RNF213, including c.14576G>A (p.R4859K) and c.14429G>A (p.R4810K), were identified as variants with a strong susceptibility for MMD. 7,18,20,21 The risk of MMD was significantly increased with the c.14576G>A (p.R4859K) variant, with an odds ratio (OR) of 190.8, 7 and homozygotes exhibited severe and diverse vasculopathy phenotypes in a Japanese study.…”

“…21 The c.14429G>A (p.R4810K) variant was suggested to have the ischemic-type MMD in the Chinese Han population. 28 Although MMD is especially prevalent in East Asia, including Korea, previous research on these RNF213 variants and their clinical implications have largely been conducted in Japan and China. This is the first study of RNF213 polymorphism associated with clinical features and long-term outcomes in Korean patients with MMD.…”