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Establishing a method for detecting HLA alleles that predispose to adverse drug reactions

A 2020/2021 Summer Studentship research project

Student: Leonie Hitchman
Supervisors: Dr Simran Maggo, Professor Martin Kennedy
Sponsor: Department of Pathology and Biomedical Science, UOC

Introduction

Many drug-induced adverse drug reactions (ADRs) are hypersensitivity reactions associated with the HLA-locus, a cluster of genes on chromosome 6.[1] Severe hypersensitivity ADRs associated with specific HLA-alleles are now well characterized for the drugs flucloxacillin (HLA-B*57:01), carbamazepine (HLA-B*15:02), and allopurinol (HLA-B*58:01) [2], and mandatory testing is required prior to prescription of abacavir (HLA-B*57:01) [3]. The HLA-gene testing is complex but recent work has indicated it is possible to use relatively simple genetic assays to identify anindividual’s HLA-type [4].

Aim

With these methods it may be possible to pre-emptively identify people at risk of these ADRs – asignificant cause of illness and death in patients, and which adds unnecessary costs to the health system [5, 6].

Method

The methods used will be predominantly polymerase chain reaction (PCR), real time PCR (RT-PCR) and Sanger sequencing. We have DNA for several consented hypersensitivity cases in our ADRs biobank (UDRUGS – Understanding Drug Reactions Using Genomic Sequencing) that are appropriate for this work [5], and positive control samples can be acquired from the Coriell Institute for Medical Research to validate the assays.

Student researcher’s component of the study

The student will gain training in commonly used molecular biology laboratory methods, ranging from basic laboratory skills to PCR and DNA sequencing. They will develop and test the methods, then apply them to samples from our UDRUGS adverse drug reaction biobank. The student will compare the data generated with data obtained by other methods.

Student prerequisites

A background in genetics or familiarity with working in a laboratory will be advantageous.