Abstract
Epilepsy is a major global issue. Epilepsy patients are treated with AED (antiepileptic drugs). Interindividual variability in drug response has been documented in several studies. The resistance to drug response may be attributed to genetic polymorphism. The current study was undertaken to investigate the CYP2C9 gene polymorphism associated with antiepileptic drug (AED) resistance in the Pakistani population. The current study included 337 individuals including 100 control subjects, 110 drug-resistant subjects, and 127 drug responders. Genomic DNA was isolated from blood, and amplification of rs1799853 (430C > T) and rs1057910 was carried out by polymerase chain reaction. Genotypes of CYP2C9 SNPs were determined by Sanger's sequencing. Astounding results were observed in the current study that none of the well-known reported SNPs of CYP2C9 was found in our Pakistani cohorts. However, a novel missense variant (c.374G > A) was found only in drug-resistant patients of the current study. According to the in silico analysis performed by PolyPhen-2, it was observed that this nonsynonymous substitution is likely to be pathogenic. The results of our study demonstrated that rs1799853 and rs1057910 may be involved in drug resistance in the Pakistani population. However, some other variants on CYP2C9 may play a critical role in AED resistance that needs to be explored.
Highlights
Epilepsy is one of the highest incidence rate CNS illnesses, characterized by repeated seizures with a variety of symptomatology [1, 2]
Recent research has increasingly shown that genetic variables, such as polymorphisms in the genes of microsomal enzymes involved in drug metabolism (CYP), have a role in the development of drug resistance in epilepsy [4,5,6,7]. e P450 cytochrome enzyme family is involved in the metabolism of the majority of medicines. e CYP2 family is in charge of the initial stage of exogenous particle metabolism
Literature evidence suggests a link between the CYP2C9 polymorphism and drug-resistant epilepsy; this link appears to be skewed by ethnicity [12,13,14,15]. e goal of the study was to identify a relationship between the SNP rs1799853 and rs1057910 of CYP2C9 gene in the Pakistani cohort
Summary
Epilepsy is one of the highest incidence rate CNS illnesses, characterized by repeated seizures with a variety of symptomatology [1, 2]. Recent research has increasingly shown that genetic variables, such as polymorphisms in the genes of microsomal enzymes involved in drug metabolism (CYP), have a role in the development of drug resistance in epilepsy [4,5,6,7]. CYP genetic variations were found in many cultures throughout the world, and the variations are responsible for the particular activity of drug-metabolizing enzymes [8]. Drugs, including antiepileptic medications, are biotransformed and eliminated by oxidation processes catalyzed by P450 cytochrome enzymes, as well as glucuronidation, in which CYP2C9 and CYP2C19 play a key role. E genetic polymorphisms of CYP2C9 and CYP2C19 impact the rate of drug metabolism, resulting in variable levels of sensitivity to prescribed therapeutic doses [9]. Literature evidence suggests a link between the CYP2C9 polymorphism and drug-resistant epilepsy; this link appears to be skewed by ethnicity [12,13,14,15]. e goal of the study was to identify a relationship between the SNP rs1799853 and rs1057910 of CYP2C9 gene in the Pakistani cohort
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