1. Haplotype structure defines effects of common DPYD variants c.85T > C (rs1801265) and c.496A > G (rs2297595) on dihydropyrimidine dehydrogenase activity: Implication for 5-fluorouracil toxicity
- Author
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Stefano Fontana, Carlo R. Largiadèr, Dominic Schärer, Stefan Schürch, Robert B. Diasio, Seid Hamzic, Christos T. Nakas, Ursula Amstutz, Didier Meulendijks, Marc Wehrli, and Steven M. Offer
- Subjects
Linkage disequilibrium ,haplotype ,Drug-Related Side Effects and Adverse Reactions ,Genotype ,Population ,610 Medicine & health ,Biology ,chemotherapy ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,DPYD ,540 Chemistry ,Dihydropyrimidine dehydrogenase ,Humans ,Pharmacology (medical) ,uracil ,030212 general & internal medicine ,education ,Dihydrouracil Dehydrogenase (NADP) ,pharmacogenetics ,Pharmacology ,education.field_of_study ,dihydropyrimidine dehydrogenase ,Haplotype ,Dihydrouracil ,Original Articles ,Molecular biology ,5‐fluorouracil ,chemistry ,Haplotypes ,570 Life sciences ,biology ,Original Article ,Fluorouracil ,Pharmacogenetics - Abstract
AIMS The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy. METHODS Plasma dihydrouracil/uracil (UH2 /U) ratios were measured as a population marker for DPD activity in a total of 1382 subjects from 4 independent studies. Genotype and haplotype correlations with UH2 /U ratios were assessed. RESULTS Significantly lower UH2 /U ratios (panova < 2 �� 10-16 ) were observed in carriers of the 4 well-studied 5-FU toxicity risk variants with mean differences (MD) of -43.7% for DPYD c.1905 + 1G > A (rs3918290), -46.0% for DPYD c.1679T > G (rs55886062), -37.1%, for DPYD c.2846A > T (rs67376798), and -13.2% for DPYD c.1129-5923C > G (rs75017182). An additional variant, DPYD c.496A > G (rs2297595), was also associated with lower UH2 /U ratios (P < .0001, MD: -12.6%). A haplotype analysis was performed for variants in linkage disequilibrium with c.496A > G, which consisted of the common variant c.85T > C (rs1801265) and the risk variant c.1129-5923C > G. Both haplotypes carrying c.496A > G were associated with decreased UH2 /U ratios (H3, P = .003, MD: -9.6%; H5, P = .002, MD: -16.9%). A haplotype carrying only the variant c.85T > C (H2) was associated with elevated ratios (P = .004, MD: +8.6%). CONCLUSIONS Based on our data, DPYD-c.496A > G is a strong candidate risk allele for 5-FU toxicity. Our data suggest that DPYD-c.85T > C might be protective; however, the deleterious impacts of the linked alleles c.496A > G and c.1129-5923C > G likely limit this effect in patients. The possible protective effect of c.85T > C and linkage disequilibrium with c.496A > G and c.1129-5923C > G may have hampered prior association studies and should be considered in future clinical studies.
- Published
- 2021
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