Evidence for epistatic interactions in antiepileptic drug resistance.
To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene-gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (P < 0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32-5.85 (P < 0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene-gene interactions underlying AED resistance.
Department of Neurology, Chonnam National University Medical School, Gwangju, Korea.
Myeong-Kyu
MK
Kim
Jason H
JH
Moore
Jong-Ki
JK
Kim
Ki-Hyun
KH
Cho
Yong-Won
YW
Cho
Yo-Sik
YS
Kim
Min-Cheol
MC
Lee
Young-Ok
YO
Kim
Min-Ho
MH
Shin
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D004843:Epistasis, Genetic / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054928:Validation Studies as Topic; D055815:Young Adult
D000927:Anticonvulsants