Population-specific DPYD variants and fluoropyrimidine toxicity risk: an analysis using public genomic databases
Introduction: Fluoropyrimidines (FP), including 5-fluorouracil (5-FU) and capecitabine, are widely used chemotherapeutic agents. However, their toxicity varies significantly among patients, often because of genetic differences in DPYD, which encodes dihydropyrimidine dehydrogenase, an enzyme crucial...
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| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Clinical Medicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1470211825001617 |
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| Summary: | Introduction: Fluoropyrimidines (FP), including 5-fluorouracil (5-FU) and capecitabine, are widely used chemotherapeutic agents. However, their toxicity varies significantly among patients, often because of genetic differences in DPYD, which encodes dihydropyrimidine dehydrogenase, an enzyme crucial for FP metabolism.1 This study examined DPYD variant frequencies across different populations to assess their impact on FP-related toxicity risk. Materials and Methods: Allele frequencies of key DPYD variants (DPYD2A, c.2846A>T, c.1236G>A, DPYD*13, and c.85T>C) were analysed using data from the 1000 Genomes Project (Phase 3) and gnomAD v2.1.1. Population groups included Indian (South Asian), East Asian (Chinese, Japanese and Korean), and African (African and African-American) cohorts.2,3 Chi-square tests and Fisher’s exact tests were used to compare allele frequencies across populations. Functional annotations were retrieved from dbSNP and ClinVar, and risk estimates were calculated using odds ratios (OR) with 95% confidence intervals (CI). Results and Discussion: Significant population differences in DPYD variant frequencies were observed1–3: • DPYD*2A (rs3918290): rare in Indian (0.05%) and East Asian populations (0%), but more frequent in African populations (0.1%); • c.2846A>T (rs67376798): absent in Indian and East Asian populations; rare in African populations; • c.1236G>A (rs56038477, HapB3): found in 1.4% of Indian populations; rare in East Asians (0%) and Africans (0.3%); • DPYD*13 (rs55886062): absent in Indian and East Asian populations; extremely rare in African populations; • c.85T>C (rs1801265): highly prevalent in Indians (24.91%), lower in East Asians (7.2%) and Africans (40.2%); • Patients carrying risk alleles had a 3.5–4.2 fold increased risk of FP-related toxicity (p < 0.05).The findings highlight higher toxicity risk in Indian and African populations resulting from distinct DPYD variant distributions. Table 1 outlines DPYD variant frequencies and Table 2 outlines risk estimates for FP-related toxicities across populations. Conclusion: Population-specific DPYD variant frequencies suggest the need for ethnicity-guided pharmacogenetic screening before FP chemotherapy.4 These findings support precision dosing strategies to minimise severe toxicity risks, particularly in Indian and African patients. Further prospective validation is warranted. |
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| ISSN: | 1470-2118 |