Is it possible to predict AED side-effects?
Grant round winners 2011
£98,122, over 18 months,
Dr Ana Alfirevic
University of Liverpool and colleagues from Liverpool, Ireland and London
Approximately two thirds of people who have epilepsy successfully control their seizures with anti-epileptic drugs (AEDs); however AEDs can sometimes have unpleasant side-effects (SEs), including fatigue, confusion and skin rashes.
Carbamazepine (CBZ) is a commonly-prescribed AED, and it is also used in the treatment of other conditions such as depression and nerve pain. Although successful in the majority of cases, it can cause SEs ranging from mild skin irritation to severe and potentially fatal blistering of the whole body; yet there is currently no way of predicting who will suffer this extreme reaction.
Dr Ana Alfirevic from the University of Liverpool and colleagues from Liverpool, Ireland and London have screened more than a million DNA variants across the human genome, in order to understand why some patients are more prone to severe blistering with CBZ than others. Prior to this, scientists in Taiwan highlighted a gene that predisposed Asian people to this hypersensitive reaction, but the group in the UK discovered that it could not be used to predict the reaction in Caucasians. The team identified a gene known as HLA-A*3101 in Caucasian people, which appeared to alter the risk of developing the SE from 5% to 26%. However, they found that only 40% of the people who had suffered a severe reaction to CBZ actually carried the gene, suggesting that other genes were involved in CBZ hypersensitivity.
Dr Alfirevic and her team have now been awarded £98,122, over 18 months, to carry out a project entitled Genetic markers for carbamazepine-induced hypersensitivity syndrome. During this study, they will sequence the DNA of 24 Caucasian people who are known to have experienced a severe reaction to CBZ in order to identify new and rare genetic variants that could be used to predict hypersensitivity. In addition, the team will genotype the DNA of 95 people with varying phenotypes of CBZ hypersensitivity, to find out whether the severity of the CBZ reaction is influenced by particular genes.
The information gained from this project could potentially lead to the development of a genetic test, which would allow clinicians to predict the people who might be harmed by CBZ. This would help to improve the safety of epilepsy treatment.