| BackgroundMoyamoya disease (MMD) is a progressive cerebrovascular disorder involving bilateral stenotic and/or occlusive lesions of the terminal portion of internal carotid arteries (ICA) and their proximal branches, and is characterized by the formation of abnormal vascular network in the base of brain. Several studied revealed that the etiology of MMD is related to genetic factors, infection and inflammatory response. Although it is still unclear, mounting evidence on ethnic predisposition and familial aggregation indicated that genetic factors may play a pivotal role in the pathogenesis of MMD. Recent studies reported that RNF213 gene may contribute to the occurrence of MMD in East Asian population. However, the MMD prevalence (1 in 10,000) is lower than the relatively high minor allele frequency of approximately 1%. Furthermore, MMD is a complex disease with genetic heterogeneity absent from a classic pattern of inheritance, and single gene locus can not sufficiently elucidate their genetic susceptibility. So we hypothesized that synergy of multiple genetic variations might confer high MMD risk via complicated gene-gene interactions.Objectives(1) To detect the genetic association between rs112735431 and rs148731719 in RNF213, rs3828610 in PDGFRB, rs3025058 in MMP-3, rs8179090 in TIMP-2 and adult MMD in Chinese Han population.(2) To explore the gene-gene interactions on adult MMD in Chinese Han population.MethodsA total of 96 consecutive unrelated patients with MMD from Nanjing Stroke Registry Program (NSRP) between April 2009 and December 2011 were recruited as the case group. All patients with MMD diagnosis were confirmed by digital subtraction angiography (DSA). Ninety-six age-and gender-matched healthy individuals from the same demographic area were recruited as controls. Genotyping was performed by improved multiple ligation detection reaction (imLDR) method. The distribution of allele and genotype frequencies between patients and controls was tested by chi-square test or Fisher’s exact test as appropriate. Interactions of different loci on MMD were evaluated by multifactor dimensionality reduction (MDR) method.Results(1) The genotype frequencies of rs112735431 (G/A+A/A, G/G) accounted for 9.37% (9/96),90.63% (87/96), and the allele A and G frequency was 5.21% (10/192), 94.79% (182/192) in MMD group, and 1.04% (1/96),98.96% (95/96),0.52%(1/192), 99.48%(191/192) in the control group, respectively. There was significant difference between two groups (OR=9.83,95%CI 1.22～79.17, P=0.018; OR=10.50,95%CI 1.33～82.80, P=0.011).(2) Compared with all of G/G genotype in MMD group, the frequencies of G/A genotype and A allele of rs148731719 in RNF213 gene were significantly higher in control groups (11.46% vs.0%, P<0.01; 11.46% vs.0%, P<0.001, respectively).(3) No significant differences were detected concerning allelic and genotypic distribution of rs3828610 in PDGFRB, rs3025058 in MMP-3, rs8179090 in TIMP-2 between patients and controls (all P>0.05).(4) MDR analysis failed to detect any significant interaction among these five loci in the occurrence of MMD (P>0.05), but the combination of three loci (rs112735431 in RNF213, rs3828610 in PDGFRB, rs3025058 in MMP-3) could have the maximum testing accuracy (57.29%) and cross-validation consistency (10/10).ConclusionThe results indicated that RNF213 rs112735431 may exert a significant influence on MMD occurrence. Compared with this overwhelming effect, the influences of PDGFRB, MMP-3, and TIMP-2 on MMD may be unremarkable in Chinese Hans. There may be no prominent interaction among these five polymorphisms on the occurrence of MMD. |
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