دور تعدد الأشكال الجينية SCN1A و UGT2B7 في الاستجابة لحمض الفالبرويك بين مرضى الصرع العراقيين

Role of SCN1A and UGT2B7 genetic polymorphism on the response to valiproic acid among Iraqi epileptic patients

Abstract
Background: Sodium-channel blocking with valproic acid (VPA) is widly used in epileptic adult and pediatric patients, the Nav1.1 channel subtypes are the major sodium channels in the central nervous system encoded by SCN1A gene. SCN1A mutations most frequently associated to a wide variety of severities hereditary epilepsy and may be major factors of individual phenotypic variances in response to AEDs. The efficacy of valproic acid (VPA) varies greatly in clinical treatment of epileptic patients has been linked to polymorphisms in genes involved in valproic acid site of action. This led to believe that the SCN1A genotype may play a role in valproic acid responsive. the second factor which is VPA steady-state target site concentration is influenced by genetic differences in its absorption, transport, and metabolism .UGT2B7 is a key enzyme in the VPA metabolism, UGT2B7 functional mutations may be one predictor of individual variability in VPA pharmacokinetics, and VPA dose in individuals should be adjusted to the therapeutic range to assure achievement and to avoid VPA adverse drug reactions such as hepatotoxicity in high-risk patients. In this study two single-nucleotide polymorphisms (SNPs) in two potential genes related to receptor site of action and drug-metabolizing enzyme were genotyped.
Aims of the study: Study the effect of genetic polymorphism in SCN1A (rs2298771) and UGT2B7 (rs7439366) genes with VPA response via determinant variability in VPA pharmacodynamics and pharmacokinetics in the Karbala province epileptic patients. Furthermore, this study investigated the effect of the UGT2B7 (rs7439366) polymorphisms on serum liver enzyme level
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to estimate genetic risk factors for VPA-induced hepatotoxicity in the Karbala province epileptic population.
Subjects and Methods: This study was performed at the Neurology consultancy at Imam AL-Hussein Medical City / Karbala –Iraq and in the out clinic patients with newly diagnosed epilepsy and other with previously AED failure treatment. patients are chosen from October 2020 to June 2021 while seeking medical care, they are chosen depending on their medical history, clinical manifestations of epilepsy and dependence on the International League Against Epilepsy’s diagnostic criteria (ILAE). It is a prospective study done on one hundred thirteen patients with epilepsy were start receiving valproic acid monothrrapy 10-15 mg/kg from the begining of the study to six months duration. Clinical data were collected monthly for each patient kept a recorded of the date, number of seizure attacks on a daily record card, re-evaluation processes were done at the third and sixth month after enrolment. 3-month retrospective baseline was used to establish the baseline seizure frequency. Blood samples were collected from each patient who had given consent for genetic testing and measurement of serum valproic acid concentration at steady state condition after three and six months, and liver enzymes test (AST), (ALT), (Total Bilirubin) before and after six months of treatments .
Results: In this study there was statistically significant association of SCN1A rs2298771 c.3184 A/G polymorphism with the differences in clinical parameters and with VPA response and there was statistically significant association of UGT2B7 (rs7439366) c.802 C/T polymorphism with the differences in serum VPA concentration and statistically association with many liver enzymes as adverse effect, while this SNP had a non-significant association with valproic acid response among epileptic patients.
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Conclusion: Genetic polymorphism of SCN1A (rs2298771) c.3184 A/G is associated with an increase in the incidence of valproic acid resistance in G mutant allele carriers and UGT2B7 (rs7439366) c.802 C/T polymorphisms may influence VPA metabolism and may be an important determinant individual VPA concentration in T allele mutant carriers . Furthermore determining UGT2B7 (rs7439366) c.802 C/T polymorphisms shows that people with the CC genotype should be monitored more closely for the possibility of hepatotoxicity.