Genetic Analysis of Cytochrome P450 Polymorphisms in Drug-responsive and Drug-refractory Epileptic patients in Telangana
Authors: Lakshmi Gudimella Sree Ranga , Mohiuddin Mohammed Khaliq , Mounika Keloth , Reddy Palkonda Shashikala , Devulapalli Krishnaveni 
Published: January 2024

Aim:
The present study aimed to evaluate the role of CYP2C9 and CYP2C19 genetic variations in drug-responsive/drug-refractory epilepsy, thereby facilitating the development of personalised drug strategies for effective treatment.

Background:
Cytochrome p450 was found to metabolize the drugs either by stimulation or by inhibition of cytochrome enzyme activity. CYP 450 genetic polymorphisms were postulated to influence the patient response to epileptic drugs by means of altered cytochrome enzyme activity resulting in varied therapeutic responses from patient to patient.

Objective:
The aim of the study is to evaluate the significance of CYP2C9 and CYP2C19 genetic variations in drug-responsive/drug-refractory epilepsy.

Methods:
A total of 65 subjects, 31 drug-refractory epilepsy cases and 34 drug-responsive epilepsy cases were included in the present study. The genetic analysis of CYP 450 2C9*2 (rs1799853), 2C9*3 (rs1057910), 2C19*2 (rs4244285) and 2C19*3 (rs4986893) polymorphisms was done by Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism. Statistical analysis was performed by online Medcalc software to evaluate the association of CYP polymorphisms with drug-responsive/drug-refractory epilepsy cases.

Results and Discussion:
In the present study, a total of 31 drug-refractory epilepsy and 34 drug-responsive epilepsy patients were enrolled. The clinical parameters like duration of seizures was significantly different in drug-refractory cases (P=0.0001) and the postictal features were significantly associated with drug-refractory cases (p=0.0124). Regarding the genetic analysis, our study results for CYP2C9*2 (rs1799853:C>T) polymorphism did not show a significant association with the drug-refractory cases. The T allele frequency was 0.03 in epileptic drug-responsive cases and was found to be 0.0 in drug-refractory cases. Genotype distribution of CC, CT and TT was found to be 93.7%, 6.3% and 0% in drug-responsive cases and 100%, 0% and 0% in drug-refractory cases, respectively. The CYP2C9*3 (rs1057910) polymorphism C-allele was not observed in both drug-refractory and responsive cases in the present study. AA genotype (100%) was found in both drug-responsive and refractory cases.
The study results for CYP2C19*2 (rs4244285) polymorphism did not show a significant association with the drug-refractory cases. The A allele frequency was 0.44 in epileptic drug-responsive cases and was found to be 0.45 in epileptic drug-refractory cases. Genotype distribution of GG, GA and AA was found to be 21.9%, 65.6% and 12.5% in drug-responsive cases and 20.83%, 70.84% and 8.33% in drug-refractory cases, respectively. The CYP2C19*3 (rs4986893) polymorphism did not show a significant association with the drug-refractory cases. The A allele frequency was 0.0 in epileptic drug-responsive cases and was found to be 0.0 in epileptic drug-refractory cases. Genotype distribution of GG, GA and AA was found to be 93.5%, 6.5% and 0% in drug-responsive cases and 100%, 0% and 0% in drug-refractory cases, respectively.

Conclusion:
In the present study, a significant difference was observed in the duration of seizures in the drug-refractory group and postictal features were significantly associated with the drug-refractory group. The genetic polymorphisms in CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3 did not show any significant association with drug refractory epilepsy. However, the study has to be extended to a large sample for the establishment of the significance of the specified polymorphisms in drug-responsive/drug-refractory epilepsy.