Predicting the risk to patients

Irish researchers have identified a gene that can predict in Europeans whether or not a patient will have a bad reaction to a widely used epilepsy medication, writes CLAIRE O'CONNELL

WE ALL know that many drugs can have side effects that range from unpleasant to, in some cases, life threatening. But imagine if a quick gene scan could tell in advance whether you are likely to have a dangerous reaction to a medication.

It’s a growing field, and earlier this year a team involving Irish researchers found a gene that can predict whether European-descent patients are at risk of a potentially life-threatening skin reaction to a commonly used epilepsy drug.

There are about 20 drugs on the market today to treat epilepsy and carbamazepine is one of the most widely prescribed, explains Dr Gianpiero Cavalleri, a biomedical research lecturer at Beaumont Hospital and the Royal College of Surgeons in Ireland.

It’s an effective medication, he notes, but there are potential downsides in a small number of patients, with about one in 20 developing a skin rash.

Smaller numbers again – roughly 20 per 10,000 exposures – will develop a hypersenstivity reaction where the skin rash extends across the entire body and organs, and particularly the liver, can start to come under stress, explains Cavalleri. “It can be life threatening, it’s a dangerous adverse reaction to the drug.”

And more rarely again – about five per 10,000 exposures – develop Stevens-Johnson syndrome.

“This is a very dangerous reaction where the rash basically turns into blisters across the entire body,” says Cavalleri. “The skin basically starts to detach from the body, and there’s a mortality rate of about 30 per cent associated with that reaction.”

Knowing an individual patient’s risk in advance can improve prescribing safety, and in 2004 researchers discovered that the immune system gene type HLA-B*1502 could predict whether a person would have serious problems on the epilepsy drug.

“It was an almost perfect predictor of Stevens-Johnson syndrome,” says Cavalleri. “But it only worked in patients of Asian ethnicity – it was no good for European-descent individuals, and that’s where we picked up the story.”

Joining forces with a group in Liverpool, Cavalleri’s team scanned the genomes of about 140 European patients who had reactions and also clinical controls, some of whom were attending the Beaumont epilepsy programme under Prof Norman Delanty.

The research, which was funded by the Health Research Board and Brainwave, also looked at a cohort of general population genomes provided by the Wellcome Trust.

And despite the relatively small numbers of patients in the study, the answer jumped out at the researchers: the predictor gene in Europeans is HLA-A*3101.

Cavalleri hopes the discovery, published in the New England Journal of Medicine earlier this year, will have an impact on how carbamazepine is prescribed. “To me there’s very little doubt that this test can provide for safer prescribing of carbamazepine,” he says. “If I was going on this drug I would like to be tested, because if you are a carrier of this allele [any one of the two or more possible forms of a gene], there’s a 25 per cent chance you are going to have a reaction to it.

“And in the best case that reaction will be a rash that is uncomfortable. In the worst case, you could end up in intensive care.”

Some hurdles remain before the test moves into wider use though, notes Cavalleri. “The clinical community like to see prospective trials, where you would test people for their HLA type before you expose them to a drug and you look at the outcome,” he says.

There’s also the issue of speed: at present, a patient would have to provide a sample and wait for up to several weeks to hear the result of the test, according to Cavalleri, but he hopes more rapid testing methods will become available.

“Ideally what we need is a cheap and rapid test – the patient licks a strip and if it turns a particular colour, then don’t prescribe the drug.”

He anticipates that more genes will be discovered that can predict drug reactions. “There are already a number of predictors that are out there for various different drugs,” he says. “And I’m not saying that every drug will have a beautiful genetic predictor of a response or a dose, but some already do and that percentage will grow.”

We may even see genome data of patients being included in their electronic records so the physician can query the database immediately and get the answer about a particular drug.

“At this point in time a patient’s genome data is not placed in the electronic patient record – we store genetic profiles on dedicated, secure severs at RCSI,” says Cavalleri.

“But I think more generally, eventually patient genetic data will be incorporated in to electronic records in a similarly secure electronic environment to that used for protecting bank account information.”

Meanwhile, the Dublin team is “chuffed” at finding the predictor gene, which could help individuals avoid bad reactions to the drug. “It’s nice to find something that makes a difference,” says Cavalleri.

“You can spend years in science and make lots of discoveries but not find something that can make a difference to people’s lives.

“This is something that can make a difference, so we are definitely proud of it.”

National Epilepsy Week runs until May 22nd. See epilepsy.ie