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. 2023 Jan;20(1):39-53.
doi: 10.2217/pme-2022-0042. Epub 2022 Nov 23.

Identification of DPYD variants and estimation of uracil and dihydrouracil in a healthy Indian population

Poornima Sivamani  1 , Vishnu Eriyat  1 , Sumith K Mathew  1 , Ashish Singh  2 , Rekha Aaron  3 , Raju Titus Chacko  2 , Anjana Joel  2 , Ratna Prabha  1 , Binu Susan Mathew  1
Affiliations

Identification of DPYD variants and estimation of uracil and dihydrouracil in a healthy Indian population

Poornima Sivamani et al. Per Med. 2023 Jan.

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.

Keywords: 5-fluorouracil; LCMS/MS; Sanger sequencing; assay validation; dihydropyrimidine dehydrogenase; dihydrouracil; genotype; pretherapeutic screening; uracil; validation.

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.

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