Translating NUDT15 pharmacogenetic testing into NHS practice

Summary

Thiopurines including mercaptopurine and azathioprine are commonly prescribed immunosuppressants but their use is limited by thiopurine-induced myelosuppression (TIM). TIM has an incidence of 7% and normally occurs within the first six months of use. Most patients with TIM are asymptomatic, but serious infections can develop with an estimated mortality of 1%.

Genetic variation of the thiopurine methyltransferase (TPMT) gene is a common cause of TIM. Before starting a thiopurine testing of TPMT genotype or enzyme activity is recommended to identify at-risk patients: in these individuals the drug may be avoided or the dose reduced. However, because TPMT variants are only found in 25% of European patients with TIM, blood test monitoring is still required to allow the early detection of TIM.

In 2019, we and others demonstrated that variants in a second gene nudix hydrolase 15 (NUDT-15); carried by about 2% of the Caucasian population, are associated with an increased risk of TIM in patients with inflammatory bowel disease (IBD). Higher carrier rates are seen in East and South Asian populations (29% and 13%). In the UK NUDT15 testing is only approved for use in patients starting a thiopurine for acute lymphoblastic leukaemia.

The overarching aim of this proposal is to have NUDT15 testing added to the National Genomic Test Directory for patients starting a thiopurine for IBD and other immune mediated diseases. This requires additional data to inform genotype-based prescribing and to build the health-economic case. To do this we will:

1. Analyse clinical and genetic data already held in the NIHR IBD BioResource.

2. Collect additional clinical and laboratory data relating to thiopurine treatment from the medical records of approximately 250 ‘cases’ who have a deleterious NUDT15 variant allele and 1,000 ‘control’ patients without a NUDT15 or TPMT variant allele.