doi:10.1038/nindia.2014.61 Published online 7 May 2014
Why do epilepsy patients develop resistance to drugs? Are any genes responsible for this? For long, scientists have been trying to answer these questions without much luck. A new study by a group of Indian scientists has sprung some surprises. A gene, earlier linked to drug resistance, actually plays a role in making patients more susceptible to epilepsy, the study says 1.
Moinak Banerjee and his colleagues at the Rajiv Gandhi Centre for Biotechnology (GCGB), Thiruvanthapuram, Kerala studied Indian epilepsy patients to find that the gene, codenamed ABCB1 rs1045642–I, increased epilepsy risk in patients.
Drug transporter genes, known to regulate entry and exit of drugs from cells, play a role in drug resistance by excessively pumping out anti-epilepsy drugs. This pumping out or 'efflux' is due to over-expression of the P-glycoprotein (P-gp) gene and other associated efflux proteins in tissues.
Banerjee and his team looked at three types of genes that could be involved in responses to epilepsy drugs — genes coding for enzymes involved in metabolising the drugs; drug transporter genes, and drug target genes. The study included 738 people from Kerala — 259 showing drug-resistance, 201 who responded to drugs, and 275 non-epilepsy controls.
They found that two genes of the ATP-binding cassette (ABC) family — ABCB1 and ABCB2 — increased the vulnerability to epilepsy rather than imparting drug resistance. They defined resistance as recurrence of seizures despite using 2-3 anti epileptic drugs or surgery for seizure control. Patients free of any seizures at a specific period of follow-up were taken as drug responsive.
The RCGB team further evaluated the two genetic variants but did not find them significant in conferring drug resistance. Instead, ABCB1 and ABCB2 were found to increase vulnerability to epilepsy and associated phenotypes in the south Indian population under study.
"We are now trying to see if the drug, on its own or in combination, can alter the patient's epigenome (chemicals that modify the effect of a gene without altering its sequence) resulting in drug resistance," Banerjee said.
Upto one-third of epilepsy cases do not respond to treatment. The problem is especially acute in developing countries such as India, where affordable generic drugs, often 15-years-old, are used in medication, Banerjee said.
The scientists suggest that the combined effects of the two genetic variants should be used to understand the range of phenotypic variants in epilepsy. These 'pharmacogenetic traits', meaning how drugs respond based on the genetic make-up, will help study drug resistance in patients better, they add.