Bioinformatics investigation of drug induced hypersensitivity reactions

Adverse drug reactions (ADRs) are of major concern to patients, health care providers and pharmaceutical companies alike because of their serious nature - in some cases there is a fatal outcome, and because of a high-rate of drug withdrawal post-marketing. The cellular and chemical mechanisms are not yet fully understood, and there are no in vitro or animal models available to investigate these reactions. Type B or “off target” reactions are thought to be immune-mediated. Recently, several striking associations have been reported between human leukocyte antigen (HLA) alleles and serious hypersensitivity reactions to antiepileptic drugs (carbamazepine), anti-AIDS drugs (abacavir) or the penicillin group of antibiotics (amoxicillin and flucloxacillin). HLA genes play a crucial role in presenting peptides to the immune system and individuals who are positive for certain HLA alleles are at increased risk of developing serious ADRs. Our research groups in bioinformatics and personalised medicine are collaborating to investigate the genetic and biochemical mechanisms underlying these reactions.

The genetic diversity of the HLA system presents considerable research challenges, which we aim to address in this project using bioinformatics and population genetics techniques. We will utilise information available on HLA allele distribution from the local DNA archive and from publically accessible databases (curated in our departments). First, it is currently unknown whether any intermediate proteins are involved in hypersensitivity reactions, which we will predict using existing software and novel machine learning techniques. Second, we wish to use population genetics techniques to understand how the implicated HLA alleles are distributed in different ethnic groups and geographical regions of the world. Third, we will use informatics techniques to study similarities between HLA alleles possessed by different individuals, to highlight new alleles not previously implicated with hypersensitivity which may represent risk factors for patients being prescribed culprit drugs.

Training:
Students will be expected to take modules from the Masters in Post-genomic science (on which ARJ is director of studies) to learn computer programming, relational databases, genomics/proteomics and so on. ARJ’s post-genomic bioinformatics research group comprises around 10 students/RAs working on a range of topics. The group has individuals with expertise in computer science, biochemistry, chemistry, bioinformatics and genetics. We have regular journal clubs, group meetings and training sessions to learn new skills, and thus is an excellent training environment for new students joining.

Students will also be expected to acquire knowledge in pharmacogenomics, molecular biology techniques, statistical genetics, basic pharmacology and epidemiology. The department of pharmacology is a large interdisciplinary department with 150 members of staff including clinicians, scientists, research nurses, clinical trials coordinators etc. There are approximately 40 postgraduate students for whom a broad spectrum of training is provided. There are several journal clubs and seminars held every week where students have an opportunity to present their work. Several workshops per year and a rolling seminar series with international guest speakers are held regularly and led by the two centres within the Department, the MRC Centre for Drug Safety Science and the Centre for Personalised Medicine.