Improving the utility of dihydropyrimidine dehydrogenase genetic testing in the NHS

Ongoing

Background 

Pharmacogenomics is the study of how genetic variation affects responses to drugs. This includes both the efficacy and safety of drugs. Pharmacogenomics is regarded as one of the most important areas for mainstreaming of genomic medicine in the NHS.   

Why this work is important 

However, the majority of genetic tests being implemented in the NHS, and worldwide, have been identified in White European ancestry populations. It is now widely acknowledged that there are significant knowledge gaps in the generalizability of biomedical discoveries to non-White populations. This is particularly acute in the area of precision medicine, where a lot of the advances have focused on genomic technologies. 

A typical example of this is dihydropyrimidine dehydrogenase (DPD) genetic testing. Dihydropyrimidine dehydrogenase is an enzyme that breaks down the anticancer drug 5-fluorouracil (5FU), and its pro-drugs, capecitabine and tegafur. A deficiency of the enzyme, either complete or partial, can lead to the inadequate breakdown of the drug, increasing its toxicity to the bone marrow. This has led to deaths in patients receiving 5FU and its congeners. Identifying that a patient has a genetic deficiency of the enzyme can be managed by reducing the dose of the drug, thereby reducing the likelihood of bone marrow suppression and other toxicities. 

There is a risk, however, that these advances could leave behind those communities who already experience ethnic health inequalities. We know that ethnic minority groups are under-represented in medical research, and this was likely among the driving factors for a lack of trust among some communities in taking the COVID-19 vaccine, among other vital medical interventions. If we want biomedical research and genomic medicine to work for everyone, there are two key priorities we must engage with now – ensuring that research is conducted in diverse populations with a range of ancestral backgrounds; and ensuring that the medical advances that result from this research is available for all.    

Aim  

The aim of this 2-year project will be to identify novel variants in the dihydropyrimidine dehydrogenase gene which cover the majority of ancestry populations being served by the NHS, and to implement these variants into the NHS genetic test directory. 

Project outputs  

  • Systematic review of DPD genetic variants 
  • In-silico functional assessment of DPD genetic variants 
  • Sequencing of the DPD gene 
  • Developing the case for widening the number of variants tested in the DPD gene 

Timelines  

Final report publication is expected in summer 2024 

Further information 

For further information please contact Dr Veline L’esperance (Senior Clinical Advisor) at info@nhsrho.org