A Study On The Association Of GABA_A Receptor Subunit Gene Single Nucleotide Polymorphisms And Refractory Epilepsy

Part oneA Correlation Study on the GABA_A Receptor Subunits Gene Polymorphism and the Susceptibility of Refractory Epilepsy.Objective: To observe and compare the genotype frequency of refractory epilepsy(RE)patients and the non-refractory epilepsy patients,investigate the relationship between the gene polymorphism of GABA_A receptor subunits and the susceptibility of RE.Methods: 109 patients with epilepsy and accepted reasonable treatments were classified according to the criteria of RE diagnosis,38 patients were classified into RE group,71 patients were classified into non-RE group.The polymorphisms of GABRA1 rs2290732,GABRA1 rs2279020,GABRA6 rs3219151 and GABRG2 rs211037 of the patients were detected and analyzed by Mass ARRAY-i PLEX and MALDI-TOF-MS,the correlation between the different genotypes,allelomorphic gene and the susceptibility of RE were assessed.Linkage disequilibrium and haplptype analyses of GABRA1 rs2290732,GABRA1rs2279020,GABRA6 rs3219151 and GABRG2 rs211037 were made with SHEsis online.Results: Genotypes GG,GA and AA in the rs2290732 locus,genotypes GG,GA and AA in the rs2279020 locus,genotypes CC,CT and TT in the rs3219151 locus and genotypes CC,CT and TT in the rs211037 locus were detected.Genotyping call rate is 98%.There were no significant differences in genotype frequencies(χ2=1.876,P=0.391)and allele frequencies(χ2=0.956,P=0.328)of rs2290732 between the two groups;The same result was got in different gene models(P > 0.05).There were also no significant differences in genotype frequencies(χ2=0.768,P=0.381)and allele frequencies(χ2=1.473,P=0.479)of rs2279020 between the two groups;The same result was also got in different gene models(P>0.05).There were no significant differences in genotype frequencies(χ2=0.404,P=0.525)and allele frequencies(χ2=1.484,P=0.476)of rs3219151 between the two groups;the same result was got in different gene models(P> 0.05).There were no significant differences in genotype frequencies(χ2=4.782,P=0.092)of rs211037,however,the genotype frequencies of the GABRG2 rs211037 T allele in the RE group was significantly higher than that in the non-RE group(χ2=5.403,P=0.020).The genotype frequencies of TT genotype and CT type of RE group in RE group were significantly higher than those in non-RE group(χ2=3.976,P=0.046).The proportion of TT genotype of RE group was significantly higher than those of non-RE group(χ2=4.795,P=0.029).Which indicates that the CT genotype and TT genotype can lead a higher risk of RE.The chromosome regions of GABRA1 gene rs2290732 locus and rs2279020 locus were contained in the same linkage disequilibrium area where there is a strong linkage disequilibrium(D’= 1.000,r2 = 0.981).Conclusion: 1.There is not any obvious relationships between the polymorphism of GABRA1 rs2290732 locus,GABRA1 rs2279020 locus,GABRA6 rs3219151 locus and RE susceptibility.2.The GABRG2 rs211037 locus mutation might be the susceptible locus of RE.The GABRG2 rs211037 T allele increased the risk of RE.3.There is a strong linkage disequilibrium between GABRA1 rs2290732 locus and GABRA1 rs2279020 locus.Part two Gamma Aminobutyric Acid Receptor Gamma 2 Subunit rs211037 Polymorphism with Susceptibility of Epilepsy: a Meta-analysis.Objective: To investigate the relationship between GABRG2 rs211037 polymorphism and susceptibility of epilepsy by using meta-analysis method.Methods: The databases of Pubmed,Embase,Web of science,Cochrane,Wan Fang,CNKI and Vip were searched and retrieval time ranged from January 31,2002 to December31,2016.STATA 14.0 was applied to calculate the OR and 95%CI and analyze the relationship between GABRG2 rs211037 polymorphism and epilepsy susceptibility.Results: According to the inclusion and exclusion criteria,there were totally 9documents included(totally 10 independent case-control studies)involved 2676 patients with epilepsy and 1788 control cases.The results of meta-analysis showed that GABRG2 rs211037 polymorphism was correlated with the risk of epilepsy in Asians(CC+CT vs TT,OR=2.272,95%CI: 1.016-2.347,P=0.042).GABRG2 rs211037 polymorphism was correlated with the risk of epilepsy in Caucasians(C vs T,OR=0.822,95%CI: 0.714-0.947,P=0.007).Conclusion: It suggest that GABRG2 rs211037 polymorphism is associated with epilepsy susceptibility.GABRG2 rs211037 genotype TT is a protective factor for the Asians.On the contrary,T allele may be a risk factor for the Caucasian.