Identification of Dpyd Variants and Estimation of Uracil and Dihydrouracil in A Healthy Indian Population

Abstract

Aim: This study aimed to identify DPYD variants and the related but previously unexplored phenotype (plasma uracil, dihydrouracil [DHU], and the DHU-to-uracil ratio) in a healthy adult Indian population. Methods: Healthy adult volunteers (n = 100) had their uracil and DHU levels measured and were genotyped for selected variants. Results: Among the nine variants studied, c.1906-14763G>A and c.85T>C were the most prevalent. Participants with any of the variants except for c.85T>C and c.1627A>G had a significantly lower DHU-to-uracil ratio and those with c.1905+1G>A variant had significantly increased uracil concentration compared with wild-type. Conclusion: Participants with five variants were identified as having altered phenotypic measures, and 40% of the intermediate metabolizers had their phenotype in the terminal population percentiles.

Plain language summary

Background: 5-fluorouracil (5-FU) is a medicine used in cancer treatment. It is eliminated from body by the enzyme DPD. Identifying deficiency in DPD before initiating 5-FU can save patients from oral, intestinal, and bone marrow toxic effects. Methods: The uracil and dihydrouracil (DHU, produced by DPD enzyme action) levels were measured and DPD gene (for identifying defects) was sequenced in 100 healthy adults. Results: Participants with DPD gene sequence that is known to be defective had higher plasma uracil levels and a low DHU-to-uracil ratio compared with those who did not have a defective gene. Conclusion: Measuring plasma uracil and DHU-to-uracil ratio can help identify people with defective DPD genes.

Keywords::

• 5-fluorouracil
• assay validation
• dihydropyrimidine dehydrogenase
• dihydrouracil
• genotype
• LCMS/MS
• pretherapeutic screening
• Sanger sequencing
• uracil
• validation

Supplementary data

To view the supplementary data that accompany this paper, please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/pme-2022-0042

Acknowledgments

The authors acknowledge all the study participants. The authors also thank D Rani (technical assistance), Madan (phlebotomist) and S Godson (maintaining the database). The authors thank C Truman, clinical pharmacist, for editing the manuscript.

Financial & competing interests disclosure

This study was funded by the Institutional Fluid Research Grant (institutional review board no. 13181) and the Department of Medical Oncology. The authors have no other affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. The funders had no influence on the outcomes of this research.

No writing assistance was utilized in the production of this manuscript.

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Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval. Informed consent has been obtained from the participants involved.

Data sharing statement

Data generated during this study is not available in the public domain, but data available with corresponding author and can be shared upon reasonable request.