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
Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED)-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype for AED-resistant epilepsy); juvenile myoclonic epilepsy (JME) (prototype for AED-responsive epilepsy); and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004). This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004) and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05) cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency for MTLE-HS in south Indian ancestry from Kerala.
References
[1]
Radhakrishnan K (2009) Challenges in the management of epilepsy in resource-poor countries. Nature Reviews Neurology 5: 323–330. doi: 10.1038/nrneurol.2009.53
[2]
Kwan P, Schachter SC, Brodie MJ (2011) Drug-resistant epilepsy. New England Journal of Medicine 365: 919–926. doi: 10.1056/nejmra1004418
[3]
Brodie M, Barry S, Bamagous G, Norrie J, Kwan P (2012) Patterns of treatment response in newly diagnosed epilepsy. Neurology 78: 1548–1554. doi: 10.1212/wnl.0b013e3182563b19
[4]
Tishler DM, Weinberg KI, Hinton DR, Barbaro N, Annett GM, et al. (1995) MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 36: 1–6. doi: 10.1111/j.1528-1157.1995.tb01657.x
[5]
Aronica E, Gorter JA, Redeker S, Van Vliet EA, Ramkema M, et al. (2005) Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain. Epilepsia 46: 849–857. doi: 10.1111/j.1528-1167.2005.66604.x
[6]
Van Vliet EA, Redeker S, Aronica E, Edelbroek PM, Gorter JA (2005) Expression of multidrug transporters MRP1, MRP2, and BCRP shortly after status epilepticus, during the latent period, and in chronic epileptic rats. Epilepsia 46: 1569–1580. doi: 10.1111/j.1528-1167.2005.00250.x
[7]
Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, et al. (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl) oxy] phenyl}-6-[5-({[2-(methylsulfonyl) ethyl] amino} methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metabolism and Disposition 37: 439–442. doi: 10.1124/dmd.108.024646
[8]
Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22: 7468–7485. doi: 10.1038/sj.onc.1206948
[9]
Kwan P, Brodie MJ (2005) Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 46: 224–235. doi: 10.1111/j.0013-9580.2005.31904.x
[10]
Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, et al. (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. New England Journal of Medicine 348: 1442–1448. doi: 10.1056/nejmoa021986
[11]
Hoffmeyer S, Burk O, Von Richter O, Arnold H, Brockm？ller J, et al. (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proceedings of the National Academy of Sciences 97: 3473. doi: 10.1073/pnas.97.7.3473
[12]
Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in Human MDR1 (P-glycoprotein): Recent Advances and Clinical Relevance&ast. Clinical Pharmacology & Therapeutics 75: 13–33.
[13]
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, et al. (2007) A“ silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315: 525–528. doi: 10.1126/science.1135308
[14]
Soranzo N, Cavalleri GL, Weale ME, Wood NW, Depondt C, et al. (2004) Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene. Genome research 14: 1333–1344. doi: 10.1101/gr.1965304
[15]
Dong L, Luo R, Tong Y, Cai X, Mao M, et al.. (2011) Lack of association between ABCB1 gene polymorphisms and pharmacoresistant epilepsy: an analysis in a western Chinese pediatric population. Brain research.
[16]
Kim DW, Kim M, Lee SK, Kang R, Lee SY (2006) Lack of association between C3435T nucleotide MDR1 genetic polymorphism and multidrug-resistant epilepsy. Seizure 15: 344–347. doi: 10.1016/j.seizure.2006.02.015
[17]
Kim DW, Lee SK, Chu K, Jang IJ, Yu KS, et al. (2009) Lack of association between ABCB1, ABCG2, and ABCC2 genetic polymorphisms and multidrug resistance in partial epilepsy. Epilepsy research 84: 86–90. doi: 10.1016/j.eplepsyres.2008.12.001
[18]
Kim YO, Kim MK, Woo YJ, Lee MC, Kim JH, et al. (2006) Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics. Seizure 15: 67–72. doi: 10.1016/j.seizure.2005.11.001
[19]
Lakhan R, Misra U, Kalita J, Pradhan S, Gogtay N, et al. (2009) No association of ABCB1 polymorphisms with drug-refractory epilepsy in a north Indian population. Epilepsy & Behavior 14: 78–82. doi: 10.1016/j.yebeh.2008.08.019
[20]
Tan N, Heron S, Scheffer IE, Pelekanos J, McMahon J, et al. (2004) Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology 63: 1090–1092. doi: 10.1212/01.wnl.0000137051.33486.c7
[21]
Kwan P, Wong V, Ng PW, Lui CHT, Sin NC, et al. (2011) Gene-wide tagging study of the association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy. Pharmacogenomics 12: 319–325. doi: 10.2217/pgs.10.183
Balan S, Sathyan S, Radha SK, Joseph V, Radhakrishnan K, et al. (2013) GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenetics and genomics 23: 605. doi: 10.1097/fpc.0000000000000000
[24]
Ramesha KN, Mooney T, Sarma PS, Radhakrishnan K (2011) Long-term seizure outcome and its predictors in patients with recurrent seizures during the first year aftertemporal lobe resective epilepsy surgery. Epilepsia 52: 917–924. doi: 10.1111/j.1528-1167.2010.02891.x
[25]
Rathore C, Sarma SP, Radhakrishnan K (2011) Prognostic importance of serial postoperative EEGs after anterior temporal lobectomy. Neurology 76: 1925–1931. doi: 10.1212/wnl.0b013e31821d74b3
[26]
Panayiotopoulos C, Obeid T, Tahan A (1994) Juvenile Myoclonic Epilepsy: A 5-Year Prospective Study. Epilepsia 35: 285–296. doi: 10.1111/j.1528-1157.1994.tb02432.x
[27]
Grunewald RA, Panayiotopoulos CP (1993) Juvenile myoclonic epilepsy: a review. Archives of neurology 50: 594. doi: 10.1001/archneur.1993.00540060034013
[28]
Vijai J, Cherian P, Sylaja P, Anand A, Radhakrishnan K (2003) Clinical characteristics of a South Indian cohort of juvenile myoclonic epilepsy probands. Seizure 12: 490–496. doi: 10.1016/s1059-1311(03)00049-9
[29]
Barrett JC, Fry B, Maller J, Daly M (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265. doi: 10.1093/bioinformatics/bth457
[30]
Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Human heredity 66: 87–98. doi: 10.1159/000119108
[31]
Mathias RA, Gao P, Goldstein JL, Wilson AF, Pugh EW, et al. (2006) A graphical assessment of p-values from sliding window haplotype tests of association to identify asthma susceptibility loci on chromosome 11q. BMC genetics 7: 38.
[32]
Lee PH, Shatkay H (2008) F-SNP: computationally predicted functional SNPs for disease association studies. Nucleic acids research 36: D820–D824. doi: 10.1093/nar/gkm904
[33]
Bournissen FG, Moretti ME, Juurlink DN, Koren G, Walker M, et al. (2009) Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: A meta-analysis. Epilepsia 50: 898–903. doi: 10.1111/j.1528-1167.2008.01858.x
[34]
Haerian B, Roslan H, Raymond A, Tan C, Lim K, et al. (2010) ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: A systematic review and meta-analysis. Seizure 19: 339–346. doi: 10.1016/j.seizure.2010.05.004
[35]
Haerian BS, Lim KS, Tan CT, Raymond AA, Mohamed Z (2011) Association of ABCB1 gene polymorphisms and their haplotypes with response to antiepileptic drugs: a systematic review and meta-analysis. Pharmacogenomics 12: 713–725. doi: 10.2217/pgs.10.212
Cavalleri GL, McCormack M, Alhusaini S, Chaila E, Delanty N (2011) Pharmacogenomics and epilepsy: the road ahead. Pharmacogenomics 12: 1429–1447. doi: 10.2217/pgs.11.85
[38]
L？scher W, Klotz U, Zimprich F, Schmidt D (2009) The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia 50: 1–23. doi: 10.1111/j.1528-1167.2008.01716.x
[39]
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, et al. (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51: 1069–1077. doi: 10.1111/j.1528-1167.2009.02397.x
[40]
Thomas R, Nair S, Banerjee M (2006) A crypto-Dravidian origin for the nontribal communities of South India based on human leukocyte antigen class I diversity. Tissue antigens 68: 225–234. doi: 10.1111/j.1399-0039.2006.00652.x
[41]
Kwan P, Baum L, Wong V, Ng PW, Lui CHT, et al. (2007) Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. Epilepsy & Behavior 11: 112–117. doi: 10.1016/j.yebeh.2007.04.013
[42]
Hung CC, Tai JJ, Lin CJ, Lee MJ, Liou HH (2005) Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response. Pharmacogenomics 6: 411–417. doi: 10.1517/14622416.6.4.411
[43]
Seo T, Ishitsu T, Ueda N, Nakada N, Yurube K, et al. (2006) ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics 7: 551–561. doi: 10.2217/14622416.7.4.551
[44]
Vahab SA, Sen S, Ravindran N, Mony S, Mathew A, et al. (2009) Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population. Drug metabolism and pharmacokinetics 24: 255–260. doi: 10.2133/dmpk.24.255
[45]
Grover S, Bala K, Sharma S, Gourie-Devi M, Baghel R, et al. (2010) Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients. Biochimie 92: 1207–1212. doi: 10.1016/j.biochi.2010.04.008
[46]
Ebid A-HIM, Ahmed MM, Mohammed SA (2007) Therapeutic drug monitoring and clinical outcomes in epileptic Egyptian patients: a gene polymorphism perspective study. Therapeutic drug monitoring 29: 305–312. doi: 10.1097/ftd.0b013e318067ce90
[47]
Nurmohamed L, Garcia-Bournissen F, Buono RJ, Shannon MW, Finkelstein Y (2010) Predisposition to epilepsy–Does the ABCB1 gene play a role? Epilepsia 51: 1882–1885. doi: 10.1111/j.1528-1167.2010.02588.x
[48]
Tang K, Ngoi SM, Gwee PC, Chua JMZ, Lee EJD, et al. (2002) Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics and genomics 12: 437. doi: 10.1097/00008571-200208000-00004
[49]
Sabeti P, Schaffner S, Fry B, Lohmueller J, Varilly P, et al. (2006) Positive natural selection in the human lineage. Science 312: 1614–1620. doi: 10.1126/science.1124309
[50]
Shaheen U, Prasad D, Sharma V, Suryaprabha T, Ahuja Y, et al.. (2013) Significance of MDR1 gene polymorphism C3435T in predicting drug response in epilepsy. Epilepsy research.
[51]
Auzmendi J, Orozco-Suárez S, Ba？uelos-Cabrera I, González-Trujano M, González E, et al.. (2013) P-Glycoprotein Contributes To Cell Membrane Depolarization Of Hippocampus And Neocortex In A Model Of Repetitive Seizures Induced By Pentylenetetrazole In Rats. Current pharmaceutical design.
[52]
Liu J, Kiehl KA, Pearlson G, Perrone-Bizzozero NI, Eichele T, et al. (2009) Genetic determinants of target and novelty-related event-related potentials in the auditory oddball response. Neuroimage 46: 809–816. doi: 10.1016/j.neuroimage.2009.02.045
[53]
Decoster J, De Hert M, Viechtbauer W, Nagels G, Myin-Germeys I, et al.. (2012) Genetic association study of the P300 endophenotype in schizophrenia. Schizophrenia Research.
[54]
Fujii T, Ota M, Hori H, Sasayama D, Hattori K, et al. (2012) Association between the functional polymorphism (C3435T) of the gene encoding P-glycoprotein (ABCB1) and major depressive disorder in the Japanese population. Journal of psychiatric research 46: 555–559. doi: 10.1016/j.jpsychires.2012.01.012
[55]
Zhang C, Kwan P, Zuo Z, Baum L (2012) The transport of antiepileptic drugs by P-glycoprotein. Advanced Drug Delivery Reviews. 64: 930–942. doi: 10.1016/j.addr.2011.12.003
[56]
Balan S, Lekshmi S, Sathyan S, Vijai J, Banerjee M, et al. (2013) Major vault protein (MVP) gene polymorphisms and drug resistance in mesial temporal lobe epilepsy with hippocampal sclerosis. Gene 526: 449–453. doi: 10.1016/j.gene.2013.05.067
[57]
Balan S, Vellichirammal NN, Banerjee M, Radhakrishnan K (2012) Failure to find association between febrile seizures and SCN1A rs3812718 polymorphism in south Indian patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Epilepsy Res. 101: 288–292. doi: 10.1016/j.eplepsyres.2012.04.009
[58]
Hung CC, Chang WL, Ho JL, Tai JJ, Hsieh TJ, et al. (2012) Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization. Pharmacogenomics. 13: 159–169. doi: 10.2217/pgs.11.141
