AIM: The present study aimed to evaluate association of genetic variants on drug response and therapy optimization parameters in patients treated with first-line antiepileptic drugs (AEDs). Genetic variants from ion channels, their functionally related genes, and synaptic vesicle cycle (SVC) genes with a potential role in epilepsy pathophysiology were thus prioritized. METHODS: A total of 12 genes from ion channels and related gene set and seven genes from SVC comprising 155 SNPs were genotyped and evaluated with drug response, dose levels, and drug levels in 408 patients with epilepsy. RESULTS: Both GABRA1 and SCN1A variants showed haplotypic and diplotypic associations in response to phenytoin (PHT). Diplotype analysis of GABRA1 variants revealed association of rs12658835|rs7735530 (AG/AG) (P-valuecorrected = 0.034, OR = 3.75, 95% CI = 1.36-11.05) and rs12658835|rs7735530|rs7732641|rs2279020 (AGCA/AGCA) (P-valuecorrected = 0.035, OR = 2.48, 95% CI = 0.96-6.41) with recurrent seizures. SCN1A haplotype rs6432860|rs3812718 (AC: P-valuecorrected = 0.022, OR = 2.72, 95% CI = 1.39-5.35) and diplotype (AC/AC: P-valuecorrected = 0.034, OR = 6.42, 95% CI = 1.10-65.76) were further observed to be associated with recurrent seizures. With respect to therapy optimization parameters, we observed significantly lower dose-adjusted drug levels at maximum dose of PHT in patients carrying AC/AC diplotype (P-value = 0.021). CONCLUSION: The results further substantiate the role of GABRA1 in PHT mode of action and contribution of SCN1A in response and therapy optimization with PHT monotherapy.
AIM: The present study aimed to evaluate association of genetic variants on drug response and therapy optimization parameters in patients treated with first-line antiepileptic drugs (AEDs). Genetic variants from ion channels, their functionally related genes, and synaptic vesicle cycle (SVC) genes with a potential role in epilepsy pathophysiology were thus prioritized. METHODS: A total of 12 genes from ion channels and related gene set and seven genes from SVC comprising 155 SNPs were genotyped and evaluated with drug response, dose levels, and drug levels in 408 patients with epilepsy. RESULTS: Both GABRA1 and SCN1A variants showed haplotypic and diplotypic associations in response to phenytoin (PHT). Diplotype analysis of GABRA1 variants revealed association of rs12658835|rs7735530 (AG/AG) (P-valuecorrected = 0.034, OR = 3.75, 95% CI = 1.36-11.05) and rs12658835|rs7735530|rs7732641|rs2279020 (AGCA/AGCA) (P-valuecorrected = 0.035, OR = 2.48, 95% CI = 0.96-6.41) with recurrent seizures. SCN1A haplotype rs6432860|rs3812718 (AC: P-valuecorrected = 0.022, OR = 2.72, 95% CI = 1.39-5.35) and diplotype (AC/AC: P-valuecorrected = 0.034, OR = 6.42, 95% CI = 1.10-65.76) were further observed to be associated with recurrent seizures. With respect to therapy optimization parameters, we observed significantly lower dose-adjusted drug levels at maximum dose of PHT in patients carrying AC/AC diplotype (P-value = 0.021). CONCLUSION: The results further substantiate the role of GABRA1 in PHT mode of action and contribution of SCN1A in response and therapy optimization with PHT monotherapy.
Authors: Paul I W de Bakker; Roman Yelensky; Itsik Pe'er; Stacey B Gabriel; Mark J Daly; David Altshuler Journal: Nat Genet Date: 2005-10-23 Impact factor: 38.330
Authors: Sarah K Tate; Chantal Depondt; Sanjay M Sisodiya; Gianpiero L Cavalleri; Stephanie Schorge; Nicole Soranzo; Maria Thom; Arjune Sen; Simon D Shorvon; Josemir W Sander; Nicholas W Wood; David B Goldstein Journal: Proc Natl Acad Sci U S A Date: 2005-04-01 Impact factor: 11.205
Authors: Berkley A Lynch; Nathalie Lambeng; Karl Nocka; Patricia Kensel-Hammes; Sandra M Bajjalieh; Alain Matagne; Bruno Fuks Journal: Proc Natl Acad Sci U S A Date: 2004-06-21 Impact factor: 11.205