Research Projects and Publications
The aim of the pharmacogenomics research programme in Liverpool is to define the mechanisms of variability in drug response (efficacy and toxicity), identify predictors, and through this develop the evidence base that will allow translation of the laboratory findings into clinical care.
We firmly believe in the fact that getting the phenotype is absolutely crucial, we do this through various study designs depending on the problem being investigated. We have in place a multi-disciplinary team with expertise in clinical, basic and social sciences, and we collaborate widely both nationally and internationally.
Epilepsy is the most common serious neurological disorder and affects almost 500,000 people in the UK. Antiepileptic drugs are the mainstay of treatment but these are ineffective in up to one third of patients. They are also associated with significant acute and chronic adverse effects and have a high propensity to elicit idiosyncratic reactions. The Wolfson Centre for Personalised Medicine holds one of the largest collections of DNA from epilepsy patients anywhere in the world, with many samples drawn from prospective studies of treatment outcomes in newly-diagnosed epilepsy. Those samples contribute to multiple ongoing research studies specifically focused on the genomics and pharmacogenomics of epilepsy. Previous projects have investigated visual field defects with vigabatrin and the efficacy of clobazam and we have an ongoing study exploring the genomics of hypersensitivity reactions with carbamazepine and lamotrigine. In addition, we are partners in the EpiPGX program funded by the European Commission (€6 million) and which aims to identify genomic biomarkers of the efficacy, tolerability and safety of antiepileptic medications. We also contribute to the EPI4K program funded by the NIH ($25 million), which is designed to explore the genetic basis of epilepsy in general.
Speed D, Hoggart C, Petrovski S, et al. A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy. Hum Mol Genet 2014; 23: 247-258.
Yip VL, Marson AG, Jorgensen AL, Pirmohamed M, Alfirevic A. HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review. Clin Pharmacol Ther 2012; 92: 757-765.
Mirza N, Vasieva O, Marson AG, Pirmohamed M. Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery. Hum Mol Genet 2011; 20: 4381-4394.
McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011; 364: 1134-1143.
Mirza NS, Alfirevic A, Jorgensen A, Marson AG, Pirmohamed M. Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors. Pharmacogenet Genomics 2011; 21: 297-302.
Hypersensitivity reactions to antiepileptic drugs, including carbamazepine (CBZ), can cause serious and potentially lethal hypersensitivity reactions in a small number of patients (1:1000 to 1:10000 patients). These reactions are characterised by skin rash, fever and multi-organ involvement. An immune pathogenesis has been implicated because: 1) drug-specific T cells have been identified in hypersensitive patients, and 2) an association has been reported between several genes within the major histocompatibility complex on Chromosome 6 that have immune function and CBZ-induced hypersensitivity (Alfirevic et al., 2006b), (Pirmohamed et al., 2001). The strongest association so far has been found between CBZ-induced Stevens Johnson Syndrome (severe form of hypersensitivity with blistering skin rash) and human leukocyte antigen HLA-B*1502 in Chinese patients. However, this does not accord with our results for hypersensitivity in a Caucasian population (Alfirevic et al., 2006a). Further work is currently underway in our department to elucidate genetic factors involved in hypersensitivity of antiepileptic drugs in clinically well-characterised patients.
FolATED: Folate Augmentation of Treatment - Evaluation for Depression
In collaboration with the Universities of Bangor, Cardiff and Swansea, North West Wales NHS Trust and University Hospital of Wales, we are providing the pharmacogenetics expertise for this Health Technology Assessment-funded clinical trial (Roberts et al., 2007).. The aim is to determine the efficacy of folic acid as an adjuvant to anti-depressant therapy in patients with moderate to severe depression. We intend to use genetic analysis to determine if polymorphisms in genes of the one-carbon folate system, and homocysteine metabolism pathway, are predictive markers of patient response to folic acid.
Warfarin is a widely used drug in the UK. It is effective but is difficult to use because of the problems in predicting the dose required to maintain adequate anticoagulation, while at the same time preventing bleeding. This variability in dose requirements is related to both genetic and environmental factors, but these are not sufficiently well-defined to be implemented in clinical practice. A 1000-patient study funded by the UK Department of Health has been conducted to investigate all the genetic and environmental factors involved in determining the response to warfarin (Kamali and Pirmohamed, 2006), (Pirmohamed, 2006). This has involved candidate gene analysis and a whole genome association scan (in collaboration with the Sanger Institute). Part of our efforts also involve an analysis of whether genotype-guided care would be cost-effective (Hughes and Pirmohamed, 2007). We are also collaborators in the International Warfarin Pharmacogenetics Consortium (IWPC) that has developed a maintenance dose algorithm that be applied to various populations globally. We have been funded by the EU-FP7 programme (EU-PACT) to undertake a randomised controlled trial of genotype-guided prescribing vs. normal clinical care in collaboration with 7 other centres in the EU.
Acute Coronary Syndrome
Acute coronary syndrome is a common condition which requires treatment with a number of drugs including β-blockers, ACE inhibitors, aspirin and clopidogrel. All of these drugs are associated with variable efficacy: identification of the best combination of drugs and doses would help in improving risk stratification in these patients, and thereby their long-term morbidity and mortality. We are currently recruiting a 1500-patient cohort from Liverpool and Blackpool which will allow an evaluation of clinical, biochemical and genetic factors involved in determining response to these drugs.
Inhaled corticosteroids in children with asthma
Inhaled corticosteroids are the mainstay of treatment in children with asthma. However, their use in some children can lead to suppression of the hypothalamic-pituitary axis, which can be manifested as an Addisonian crisis when the child is admitted with an inter-current infection, delayed growth, or more subtly as tiredness and lethargy. Our aim here is to define cohorts who are on inhaled corticosteroids, assess them for adrenal suppression using gold-standard methods, and from this identify genetic and clinical factors responsible for susceptibility. This study is being conducted at the Royal Liverpool Children’s Hospital, and has been adopted by the UK Medicines for Children Research Network.
NSAID-induced peptic ulceration
Non-steroidal anti-inflammatory agents (NSAIDs) are widely used drugs for relief of pain and inflammation. Unfortunately, they can lead to gastric and duodenal ulceration, which is common, and due to a number of factors that affect gut mucosal integrity, and repair. Patients who are undergoing endoscopy are recruited; some patients have biopsy which will be subject to microarray analysis, while genetic factors will be evaluated by the most up-to-date genotyping strategy.
We are part of the DILIGEN network originally funded by the Department of Health (PI: Prof Ann Daly, Newcastle University). This network has been identifying and recruiting patients with drug-induced liver injury (DILI) with a number of drugs, principally the beta-lactam antibiotics co-amoxiclav and flucloxacillin, and anti-TB drugs. We are also collaborating with the Serious Adverse Event Consortium.
The acetylcholinsterase inhibitor tacrine was used in Alzheimer’s disease, but therapy was complicated by the occurrence of transient liver injury manifested as an elevation in serum alanine aminotransferase (ALT) in up to 50% of patients. Our studies have identified that genetic variants in the ATP-binding cassette, subfamily B, member 4 (ABCB4) (Alfirevic et al., 2007), and interleukin 6 (Carr et al., 2007) genes predispose to tacrine transaminitis. We have adopted both a candidate gene panel approach and an unbiased method of candidate gene identification using hepatic gene expression data from a rodent model of tacrine hepatoxicity.
Studies with the Liverpool Biomedical Research Centre in Microbial Diseases
We are involved in the safety theme in the Liverpool Biomedical Research Centre that was funded by the NIHR. Three projects involve the use of pharmacogenetic techniques:
- Penicillin allergy – in addition to the use of proteomic techniques, we are also recruiting patients with a history of penicillin allergy who will then be assessed for genetic predisposing factors.
- HIV-lipodystrophy – this is a complication of treatment with highly active antiretroviral therapy, manifest as fat redistribution,hyperlipidemia, insulin resistance and increased risk of coronoary artery disease. We have previously shown an association with the TNF locus (Maher et al, 2002).
- Clostridium difficile associated toxin disease (CDTD) - CDTD is a major public health problem in many developed countries, partly because of over-use of broad spectrum antibiotics. However, not every patient develops CDTD. The disease requires the presence of the organism, broad spectrum antibiotic therapy, and ill-defined host susceptibility factors; our research aims to evaluate the latter.
Nevirapine use in Malawi
Nevirapine is the mainstay of antiretroviral therapy in Malawi. However, its use is associated with the occurrence of hypersensitivity reactions and/or hepatotoxicity. Dosing is based on a standard regime, but in some patients under-dosing and overdosing may also be occurring. We have recruited 1000 patients in Malawi, with the aim of defining factors that affect inter-individual variability in drug disposition and drug bioactivation, and to define the genetic factors associated with predisposition to the idiosyncratic adverse drug reactions.