1. Genetic Susceptibility Study Of Chinese Mesial Temporal Lobe Epilepsy 2. Paroxysmal Kinesigenic Choreoathetosis: Evidence Of Linkage To Chromosome 16p11.2-q12.1 In Four Chinese Families

BackgroundsEpilepsy is one of the most common neurological disorders with 5～10‰of morbidity in developed countries.Prevalence rate of epilepsy in China is 3.5～4.8‰and mesial temporal lobe epilepsy(MTLE) possesses the highest incidence of adult onset focal seizures. Sporadic MTLE is regarded as a complex disease attributed to the interaction of genetic factors and environmental factors.Genetic variations can affect the epileptogenesis, development and prognosis of MTLE by multiple facets including the susceptibility of seizure on-set,medication response and seizure features.Head trauma,brain infection, birth injury,and febrile convultion are environmental factors of MTLE.Although the view that the paroxysmal disorder including epilepsy is a channolapathy disease is accepted,the gene involved in genetic susceotibility of MTLE is still unknown.This study was then planned to test the hypothesis that one or more variants inγ-aminobutyric acid type B receptor 2(GABBR2),γ-aminobutyric acid type B receptor 1(GABBR1),prion protein (PRNP) and potassium large conductance calcium-activated channel subfamily M beta member 4(KCNMB4) genes are associated with sporadic MTLE using tag SNPs method in a Han Chinese MTLE patients and non-epilepsy control subjects design.MethodsEligible MTLE patients and non-epilepsy control subjects were recruited in this study. Polymorphisms including tag SNPs of 4 candidate genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP),and then the relationship between allele/gentotype distribution and MTLE presence were analyzed, the effect to disease phenotype was also discussed. Results1.Association of tag SNPs in GABBR2 gene with MTLEWe assessed the association of each genotype by logistic regression analyses adjusting for sex in additive,dominant and recessive genetic model in a 315-case-and-318-control sample set.Three tag SNPs of GABBR2 were found to be associated with the risk of MTLE. rs967932 A-allele showed an increased risk of MTLE when applying an additive and dominant genetic model(P = 0.018,OR = 1.305,95%CI 1.048-1.624 and P = 0.003,OR = 1.667,95%CI 1.186-2.343).rs1999501 of GABBR2 gene showed an increased risk of MTLE with a dominant model(P = 0.033,OR = 1.469,95%CI 1.032-2.090),while rs944688 conferred a reduced risk of disease with a dominant model(P = 0.025,OR = 0.608,95%CI 0.393-0.939).After a Bonferroni correction,only rs967932 A-allele significantly increased the risk of MTLE in a dominant model(P = 0.036).There was no significant difference in genotype frequencies between cases and controls for rs3780428. Comparison analysis of haplotype frequencies demonstrated that the frequency of haplotype G-C-A-C(rs3780428-rs1999501-rs967932-rs944688) was significantly increased in MTLE patients compared to controls(12.26%vs.6.51%,P = 0.0004).After a Bonferroni correction was applied,haplotype G-C-A-C was still the significant risk factor (P = 0.0024,OR = 2.028,95%CI 1.359-3.024).Analyses of the relationship between haplotype G-C-A-C and clinical phenotypes revealed that haplotype G-C-A-C was associated with an earlier onset age compared to other haplotype(14 years vs.19 years,P = 0.028)2.Association of tag SNPs in GABBR1 gene with MTLEWe assessed the association of each genotype by logistic regression analyses adjusting for sex in additive,dominant and recessive genetic model in a 315-case-and-318-control sample set,and one tag SNPs of GABBR1 were found to be associated with the risk of MTLE.rs29259 C-allele showed an reduced risk of MTLE when applying an dominant genetic model(P = 0.046,OR = 0.697,95%CI 0.488-0.994),but did not reach a significant level when Bonferroni correction was applied(P = 0.276).There was no significant difference in genotype frequencies between cases and controls for rs29261. The G1465A genotype of all subjects was GG.Comparison analysis of haplotype frequencies demonstrated that no haplotype of rs29259-rs29261 was significantly different in MTLE patients compared to controls.When MTLE patients were subgrouped according to the presence of hippocampal sclerosis(HS),still no differences were detected between subgroups at the genotypes/alleles of rs29259 and rs29261.3.Association of polymorphisms in PRNP gene with MTLEThe frequency of V allele was 0.94%in 320 MTLE cases and 1.61%in 558 controls. No significant differences in the genotype(P = 0.24) or allele(P = 0.24) frequencies of M129V polymorphism in MTLE patients and controls were observed.Even when the samples were stratified by gender,no significant association was noted between the cases and controls.By sub-grouping control subjects in 2 age groups,i.e.,individuals aged 13-49 years(34.8%) and those aged 50-89 years(65.2%),additional statistical analysis of the relation of the genotype and M129V allele to age was obtained.No significant difference was observed between MTLE patients and controls with regard to genotype distribution(P = 0.76 and 0.43 respectively) or allelic frequency(P = 0.06 and 0.43 respectively).We also analyzed clinical features according to the presence of 129V allele in MTLE patients.No apparent differences were found between 6 patients heterozygous for M129V and others with the MM genotype with respect to age,ratio of males,age at onset,aura,family history,antecedent FC,MRI signs,and response to medication.4.Association of tag SNPs in KCNMB4 with MTLEWe assessed the association of each genotype by logistic regression analyses adjusting for sex in additive,dominant and recessive genetic model in a total 321-cases-and-496-control sample set,and none of three tag SNPs KCNMB4 were found to be associated with the risk of MTLE.Comparison analysis of haplotype frequencies demonstrated that no haplotype of rs787931-rs9634299-rs10784846 was significantly different in MTLE patients compared to controls.When MTLE patients were subgrouped according to the presence of hippocampal sclerosis(HS),still no differences were detected between subgroups at the genotypes/alleles of rs787931,rs9634299 or rs10784846.ConclusionsIn summary,GABBR2,GABBR1,PRNP and KCNMB4 were selected as candidate genes to explore their genetic roles to MTLE by a tag-SNP-based method in a Han Chinese MTLE patients and non-epileptic control subjects design.It suggested that A-allele of GABBR2 rs967932 is the at-risk factor to MTLE,and the role of GABBR1, PRNP and KCNMB4 in the aeteology of MTLE may be small or modest.