| Epilepsy is a common chronic neurological disease.At present,there are about 46 million active epilepsy patients worldwide,causing a great social burden.At present,antiepileptic drugs are still the most important clinical treatment options for epilepsy,and the efficacy of antiepileptic drugs in different patients with epilepsy varies greatly in clinical practice.Therefore,this study further carried out a multivariate correlation analysis study on the pharmacodynamics（PD）of antiepileptic drugs,and the results showed that the pharmacokinetics（PK）of antiepileptic drugs had a significant effect on the differences in drug efficacy between individuals.Furthermore,genetic factors are also considered to be an important factor of individual differences in PK and PD in patients with epilepsy except for the clinical factors included in the study.Besides,there is no genome-wide association analysis（GWAS）study on the clearance and efficacy of antiepileptic drugs presently.In this study,valproic acid,the most commonly used antiepileptic drug in China,was selected to conduct GWAS studies on its PK and PD,respectively,to identify potential gene loci related to the efficacy and clearance of valproic acid in Chinese epilepsy patients.Objective:1.To explore the clinical influencing factors causing individual differences in clinical efficacy and pharmacokinetics of antiepileptic drugs.2.Based on GWAS,the SNPs related to the efficacy and clearance of valproic acid were screened to find the genetic variants significantly associated with valproic acid PK and PD.The identified genetic variants were validated.Method:1.This study followed up the patients with epilepsy before and after the use of antiepileptic drugs for a period of 4 years,and to record the demographic data,disease characteristics,and medication treatment.The degree of seizure reduction was used as a measure of the efficacy of antiepileptic drugs,and the possible influencing factors were analyzed.2.According to the study design,blood samples were collected from patients with epilepsy taking valproic acid at multiple sampling points throughout the day,and the plasma concentration of valproic acid was measured by gas chromatography.Combined with the individual information of patients,a population pharmacokinetic model was established.Individual clearance rates were also calculated for each patient.3.743722 SNPS were genotyped by Infinium Asian Screening Array-24 v1.0 Bead Chip after DNA extraction and purification.After quality control of genotyping results and genotyping imputation,individual clearance rate of valproic acid was used as the PK phenotype data for GWAS.The SNPs significantly associated with the PK of valproic acid in patients with epilepsy were screened(P<1×10-5).4.The efficacy of valproic acid in patients with epilepsy was collected as the data of PD phenotype.After quality control of genotyping results and genotype filling,a GWAS was conducted to screen SNPs significantly associated with the PD of valproic acid in patients with epilepsy(P<8.07×10-9).5.In order to validate the SNPs found to be significantly associated with valproic acid PK/PD from GWAS,patients with epilepsy who had been taking valproic acid for more than three months were also collected as the validation group.The representative SNPs found to be significantly associated with PK/PD in the GWAS were genotyped by Mass ARRAY technique in the validation group samples,and the results were compared with the PK/PD phenotype data of the validation group to screen the validated SNPS associated with PK/PD of valproic acid（P<0.05）.Result:1.Clinical records of 2027 epilepsy patients were finally included in this study.The plasma concentration of valproic acid was significantly correlated with PD（P<0.01）.The efficacy in female patients was better than that in male patients（OR=1.318[1.033-1.682],P<0.05）,including the polytherapy of valproic acid and oxcarbazepine was significantly better than monotherapy of each AEDs（OR=1.93[1.024-1.037],P<0.01）.However,there was no significant difference in the efficacy between other polytherapy and monotherapy in patients with epilepsy（P>0.05）.2.259 patients with epilepsy who taking valproic acid were further collected,and the population pharmacokinetic models of two dosage forms of valproic acid sustained-release tablets and oral liquid were established to describe the pharmacokinetic characteristics of valproic acid.It has been verified that the model has good predictive ability and stability.According to this model,the clearance rate of valproic acid in individual epileptic patients was estimated.3.A total of 5813554 SNPs in 222 samples were included in the GWAS analysis after quality control and genotype filling processing of the original genotyping data,and 44 SNPs were significantly associated with the PK of valproic acid and 254 SNPs were significantly associated with the PD of valproic acid.4.368 and 590 samples were included as the validation groups of PK and PD,respectively,and the phenotypic values of PK/PD in the validation group were calculated.According to the GWAS results of PK/PD,8 and 22 SNPs were selected for genotyping,respectively.The rs55888542 and rs72660653 polymorphisms located in GLIS1 gene were significantly associated with the clearance rate of valproic acid in patients with epilepsy（P<0.05）.The rs79628500 polymorphism in UBE2E2gene was significantly associated with the efficacy of valproic acid（P<0.05）.Conclusion:This study found that rs55888542 and rs72660653 polymorphism in GLIS1 were significantly associated with the PK of valproic acid in patients with epilepsy.The rs79628500 polymorphism in UBE2E2 gene is significantly associated with the efficacy of valproic acid. |
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