Researchers working in the field of pharmacogenomics (methods that investigate how a person’s genetic make-up influences their response to prescribed drugs) investigated how susceptible individuals could be to drug induced liver injury (DILI) following administration of the drug flucloxacillin. Flucloxacillin is an antibiotic used for the treatment of staphylococcal infection; however in a very small number of patients (predicted to be 8.5 in 100,000) the use of this drug leads to DILI within 2 months.
The impact of an individual’s genetic make-up on flucloxacillin-induced DILI was previously unknown and the researchers addressed this using a genome wide association study (GWAS). From person to person there are many single position differences within our genetic code; these are termed single nucleotide polymorphisms (SNPs). GWAS is a technique that exploits these differences to classify frequently similar regions of DNA that may be associated with a disease or trait among affected individuals (cases) when you compare their DNA to a “normal” non-affected group (controls), matched for age, gender and ethnic background. The analysis is most commonly carried out using a SNP array, this is a technology designed to represent all common SNPs within the human genome in tiny fragments located in set positions on a solid surface. If an individual’s DNA is fragmented and added to the SNP array then the DNA will only bind to fragments that match. The position of these matching fragments, and thereby the SNPs are recorded for each individual.
This experimental approach was taken to compare 58 flucloxacillin DILI cases and 282 controls. The case group had an average age of 63 years and contained more females than males. The DNA from all the individuals was read on an Illumina 1M BeadChip SNP array containing over 1 million SNP markers. When the case and control groups were compared using statistical analysis it emerged that there was genetic association between flucloxacillin DILI cases and HLA-B*5701, a variation of a gene involved in the immune system. HLA-B*5701 is fairly common in Northern European populations. Although only 1 in 500-1000 individuals with this genetic variation will go on to develop DILI following flucloxacillin treatment, it’s estimated that 85% of suspected flucloxacillin DILI cases will carry HLA-B*5701. Since the risk of DILI appears to increase with age, diagnostic testing for the HLA-B*5701 gene variation in suspected flucloxacillin DILI cases could provide evidence that would determine if a patient should be switched to an alternative antibiotic in the treatment of a staphylococcal infection.
A similar study has also been published by the same group investigating Amoxicillin-Clavulanate DILI and there is on-going research into DILI from nonsteroidal anti-inflammatory drugs (NSAIDs) and statins where there is also an age associated risk. This is a perfect example of how the BRC is applying genomic techniques in the form of GWAS and making it directly relevant to the welfare of the older patient as well as diagnostic practice.