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Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population
Zhiyuan Wu1, Hanqiang Jiang, Lei Zhang
1Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Background:
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: 8.6~156.6, 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.
Insights
RNF213 gene mutations significantly increase Moyamoya disease risk in Han Chinese. The R4810K mutation is linked to ischemic MMD, while A4399T is associated with hemorrhagic MMD, highlighting genetic heterogeneity.
Area of Science:
- Genetics
- Neurology
- Cerebrovascular Diseases
Background:
- Moyamoya disease (MMD) is a rare cerebrovascular disorder causing progressive artery occlusion.
- Genetic factors are increasingly implicated in MMD etiology.
- Previous studies linked the RNF213 gene to MMD in Japanese populations.
Purpose of the Study:
- To investigate the association between RNF213 gene mutations and MMD susceptibility in the Chinese Han population.
- To validate the R4810K mutation and identify other RNF213 mutations in this cohort.
Main Methods:
- A case-control study was conducted with 170 MMD cases and 507 controls.
- Genotyping of the RNF213 R4810K mutation was performed.
- Genomic sequencing was used to identify other RNF213 variants.
Main Results:
- The RNF213 R4810K mutation was significantly more frequent in MMD cases (13%) than controls (0.4%), increasing MMD risk (OR=36.7).
- R4810K allele frequency differed between ischemic and hemorrhagic MMD subtypes.
- Eight novel RNF213 variants were identified, including A4399T, which was associated with MMD (OR=2.0), particularly hemorrhagic MMD (OR=2.8).
Conclusions:
- RNF213 mutations are associated with MMD susceptibility in Han Chinese.
- The R4810K mutation is linked to ischemic MMD, while A4399T is associated with hemorrhagic MMD.
- The identification of novel variants underscores the genetic heterogeneity of MMD.
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