Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility

Abstract

BackgroundPharmacotherapy of epilepsy including antiepileptic drugs (AEDs) is one of the main treatment approaches. As a biological target, sodium channels (Nav channels) and glutamate receptor genes are playing a major role in the etiology and treatment of epilepsy.ObjectiveThis study aims to investigate the genetic associations of certain genetic polymorphisms with increased risk of epilepsy susceptibility and variability in response to AEDs treatment in a Jordanian Arab population.MethodA pharmacogenetics and case-control study on 296 unrelated epileptic Jordanian patients recruited from the pediatric neurology clinic at the Queen Rania Al-Abdullah Hospital (QRAH) in Amman, Jordan and 299 healthy individuals was conducted. Children up to 15 years old which receiving AEDs for at least three months were scanned for genetic association of 7 single nucleotide polymorphisms (SNPs) within three candidate genes (SCN2A, SCN3B and GRM4) with epilepsy susceptibility.ResultsSCN2A rs2304016 (P = 0.04) and GRM4 rs2499697 (P = 0.031) were statistically significant with generalized epilepsy. Haplotype of CAACG GRM4 was genetically associated with epilepsy and partial epilepsy (P = 0.036; P = 0.024, respectively). This study also found that TGTAA genetic haplotype formed within GRM4 gene was associated with generalized epilepsy susceptibility (P = 0.006). While, no significant linkage of SCN3B rs3851100 to either disease susceptibility or drug responsiveness was found.ConclusionThis study identified no significant associations of allelic or genotypic SNPs with the susceptibility of epilepsy and medication response with an exception of rs2304016 and rs2499697 SNPs that were associated with the generalized type of epilepsy among Jordanian population. Further studies are required in different populations to confirm our results and identify genetic factors that involved in susceptibility and treatment response.

Association Between SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 Polymorphisms and Responsiveness to Antiepileptic Drugs: A Meta-Analysis

“…Nav channels are the main targets of many first-line AEDs ( 31 – 34 ). SCN1A and SCN2A genetic variants may change the response to AEDs ( 25 ). SCN1A rs2298771 (c.3184A>G/p.Thr1067Ala), located in the SCN1A exon region, is an A-to-G variant, which causes the substitution of alanine for threonine ( 27 ).…”

“…In contrast, Shi et al ( 5 ) found that the rs2304016 G allele increased the risk of VPA resistance. Moreover, some studies have shown that the rs2304016 polymorphism does not affect the risk of AED resistance ( 7 , 10 , 14 , 21 – 23 , 25 ).…”

Genetic Polymorphisms of Pharmacogenes among the Genetically Isolated Circassian Subpopulation from Jordan

“…However, this study encountered some limitations such as small sample size and focusing on genotyping certain polymorphisms. Moreover, only a few pharmacogenetic studies [33][34][35][36][37][38][39][40][41][42][43][44] have been conducted in Jordan. Therefore, more studies are recommended in this topic by investigating other VIP variants in different candidate genes.…”

Regulation and functional consequences of mGlu4 RNA editing

“…Genome wide association studies (GWAS), immunohistochemical, and pharmacologic studies strongly suggest a role for mGlu4 in epilepsy, and the GRM4 gene (human chromosome 6, band p21.3) resides within a known susceptibility locus known for juvenile myoclonic epilepsy 300,363 . GWAS analysis has discovered a moderate but significant association of the GRM4 SNP, rs2029461, with both generalized 364 and juvenile myoclonic epilepsy [365][366][367] . An additional SNP, rs2451334, is significantly associated with response to anti-epileptic drugs (AEDs), underscoring the importance of mGlu4 in epilepsy treatment 364 .…”