Gene-wide tagging study of the effects of common genetic polymorphisms in the α subunits of the GABA(A) receptor on epilepsy treatment response.
OBJECTIVE
We aimed to identify the effect of SNPs in the α-subunits of GABAA receptors on epilepsy treatment outcomes by using a gene-wide tagging method.


METHODS
There were 720 epileptic patients included in the present study. A total of 136 tagging SNPs in GABRA1, GABRA2, GABRA3, GABRA4, GABRA5 and GABRA6 were genotyped by Illumina(®)GoldenGate(®) Genotyping platform. Clinical information, such as prescribed antiepileptic drugs, height, weight, epilepsy syndrome classification, etiology, number of attacks, renal function and liver function were collected. The associations between SNPs and epilepsy treatment outcomes were analyzed using SAS(®) version 9.1.3. Both multivariate logistic regression and multifactor dimensionality reduction analyses were performed.


RESULTS
The results of single gene effects did not remain significant after Bonferroni's corrections. Further multivariate logistic regression and multifactor dimensionality reduction analyses of interactions between these genes showed that under adjustment of clinical factors, the epilepsy treatment outcomes were significantly associated with the genotype combinations of GABRA1 rs6883877, GABRA2 rs511310 and GABRA3 rs4828696 (p < 0.0001; adjusted r(2) = 0.149).


CONCLUSIONS
Our results indicated that genetic variants in the α subunits of GABA(A) receptors may interactively affect the treatment responses of antiepileptic drugs. Further replication using an independent sample collection would be essential to confirm our findings.
Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan and Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan.
Chin-Chuan
CC
Hung
Pei-Lung
PL
Chen
Wan-Min
WM
Huang
John Jen
JJ
Tai
Tsung-Jen
TJ
Hsieh
Shih-Torng
ST
Ding
Yow-Wen
YW
Hsieh
Horng-Huei
HH
Liou
D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D016896:Treatment Outcome
D000927:Anticonvulsants; D011963:Receptors, GABA-A