Open AccessEvaluating the Role of Genetic Variants on first‐line antiepileptic drug response in North India: Significance of SCN 1A and GABRA 1 Gene Variants in Phenytoin Monotherapy and its Serum Drug Levels
Author(s) -
Baghel Ruchi,
Grover Sandeep,
Kaur Harpreet,
Jajodia Ajay,
Rawat Chitra,
Srivastava Ankit,
Kushwaha Suman,
Agarwal Rachna,
Sharma Sangeeta,
Kukreti Ritushree
Publication year - 2016
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12570
Subject(s) - medicine , pharmacogenomics , phenytoin , haplotype , epilepsy , pharmacogenetics , gene , genetic variation , pharmacology , snp , drug , single nucleotide polymorphism , genetics , bioinformatics , biology , genotype , psychiatry
Summary 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 ( AED s). 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 SNP s were genotyped and evaluated with drug response, dose levels, and drug levels in 408 patients with epilepsy. Results Both GABRA 1 and SCN 1A variants showed haplotypic and diplotypic associations in response to phenytoin ( PHT ). Diplotype analysis of GABRA 1 variants revealed association of rs12658835|rs7735530 ( AG / AG ) ( P ‐value corrected = 0.034, OR = 3.75, 95% CI = 1.36–11.05) and rs12658835|rs7735530|rs7732641|rs2279020 ( AGCA / AGCA ) ( P ‐value corrected = 0.035, OR = 2.48, 95% CI = 0.96–6.41) with recurrent seizures. SCN 1A haplotype rs6432860|rs3812718 ( AC : P ‐value corrected = 0.022, OR = 2.72, 95% CI = 1.39–5.35) and diplotype ( AC / AC : P ‐value corrected = 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 GABRA 1 in PHT mode of action and contribution of SCN 1A in response and therapy optimization with PHT monotherapy.