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| COMMENTARY |
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| Year : 2014 | Volume
: 60
| Issue : 3 | Page : 239-240 |
ABCB1 variant provides important leads for pharmacogenetics of epilepsy
MN Phani, K Satyamoorthy
School of Life Sciences, Manipal University, Manipal, Karnataka, India
| Date of Web Publication | 14-Aug-2014 |
Correspondence Address:
Dr. K Satyamoorthy
School of Life Sciences, Manipal University, Manipal, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
How to cite this article:
Phani M N, Satyamoorthy K. ABCB1 variant provides important leads for pharmacogenetics of epilepsy. J Postgrad Med 2014;60:239-40 |
In this issue of JPGM, Taur et al. have reported an interesting finding on the effect of ABCB1C3435T polymorphism along with the P-glycoprotein activity influencing the response to antiepileptic drugs in epileptic patients of Indian origin. [1] Epilepsy is one of the most prevalent neurological disorders, affecting approximately 50 million people. Routinely available antiepileptic drugs are only 50-60% effective and one third of epileptic patients experience resistance to commonly used antiepileptic drugs. The study by Taur et al. is important in the context of India, due to lack of significant data to correlate genetic variants of drug-metabolizing enzyme genes (Pharmacokinetic), drug target genes (Pharmacodynamic) and clinical responsiveness to antiepileptic drugs in patients with epilepsy. Considering the high prevalence of the disease and increase in non-responders to antiepileptic drugs, several studies in epilepsy have been performed in different populations with an effort to integrate the principles of pharmacogenomics. However, these studies have often been difficult to interpret owing to a lack of reproducibility of the results. The probable reason for this could range from stratification of population, sample size, inconsistency in phenotypic definition and heterogeneous clinical symptoms.
The study by Taur et al. is important for two reasons - 1) The authors have evaluated the key drug-metabolizing enzyme genes CYP2C9, CYP2C19 (Pharmacokinetic) and drug target gene ABCB1 (Pharmacodynamic) and secondly, they have attempted to correlate the activity of P-glycoprotein along with the plasma drug concentrations for treatment response in patients with epilepsy. The authors have gone on to show that P-glycoprotein activity and C3435T polymorphism of ABCB1, but not polymorphisms of CYP2C9 and CYP2C19, appear to influence response to antiepileptic drugs. Though these findings are generally in agreement with the study by Siddiqui et al., [2] the reports from other Indian studies (Balan et al., Lakhan et al., Vahab et al.,) [3],[4],[5] have shown conflicting results though. To further confound the matter, a recent report on South Indian population by Shaheen et al. [6] has shown the association of TT genotype of ABCB1 with drug-resistant epilepsy.
One of the key results of Taur et al. could be the lack of association between P-glycoprotein activity and ABCB1 genotype, and dose adjusted plasma antiepileptic drug concentrations (phenytoin, phenobarbital, or carbamazepine). These results may also suggest that ABCB1 polymorphisms may influence the antiepileptic drug responsiveness independent of changes in plasma concentrations. This result can be further interrogated in larger independent studies. Antiepileptic drugs often affect more than one gene products and thus these markers can be best used together to predict the outcome of the drug response. With an ever increasing number of mixed reports due to small effect size of the variants, there is a need to integrate other genomic variants such as copy number variations and epigenetics. Haplotype study, gene-gene and gene-environment interactions could also be considered to gain deeper understanding of genetics of epilepsy in general and role of ABCB1 in particular to study the drug response.
While the paper by Taur et al. provides valuable information to the researchers in the field of epilepsy to carryout large genetic epidemiological studies by taking into account all the confounding factors including environmental and other genetic variables, a lot more work still remains to be done.
| :: References | |  |
| 1. | Taur SR, Kulkarni NB, Gandhe PP, Thelma BK, Ravat SH, Gogtay NJ, et al. Association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and activity of P-glycoprotein with response to anti-epileptic drugs. J Postgrad Med 2014;60:265-9. 
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| 2. | Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003;348:1442-8.
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| 3. | Balan S, Bharathan SP, Vellichiramal NN, Sathyan S, Joseph V, Radhakrishnan K, et al. Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance. PloS One 2014;9:e89253.
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| 4. | Lakhan R, Misra UK, Kalita J, Pradhan S, Gogtay NJ, Singh MK, et al. No association of ABCB1 polymorphisms with drug-refractory epilepsy in a north Indian population. Epilepsy Behav 2009;14:78-82.
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| 5. | Vahab SA, Sen S, Ravindran N, Mony S, Mathew A, Vijayan N, et al. Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population. Drug Metab Pharmacokinet 2009;24:255-60.
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| 6. | Shaheen U, Prasad DK, Sharma V, Suryaprabha T, Ahuja YR, Jyothy A, et al. Significance of MDR1 gene polymorphism C3435T in predicting drug response in epilepsy. Epilepsy Res 2014;108:251-6.
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