Journal article
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
British journal of clinical pharmacology, Vol.87(8), pp.3234-3243
08/2021
DOI: 10.1111/bcp.14742
PMCID: PMC8359980
PMID: 33491253
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 (UH 2 /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 UH 2 /U ratios were assessed. Results Significantly lower UH 2 /U ratios (p anova < 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 UH 2 /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 UH 2 /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.
Details
- Title: Subtitle
- 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
- Creators
- Seid Hamzic - University Hospital of BernDominic Schärer - University Hospital of BernSteven M. Offer - Mayo ClinicDidier Meulendijks - The Netherlands Cancer InstituteChristos Nakas - University Hospital of BernRobert B. Diasio - Mayo ClinicStefano Fontana - Swiss Red CrossMarc Wehrli - University Hospital of BernStefan Schürch - University of BernUrsula Amstutz - University Hospital of BernCarlo R. Largiadèr - University Hospital of Bern
- Resource Type
- Journal article
- Publication Details
- British journal of clinical pharmacology, Vol.87(8), pp.3234-3243
- DOI
- 10.1111/bcp.14742
- PMID
- 33491253
- PMCID
- PMC8359980
- ISSN
- 0306-5251
- eISSN
- 1365-2125
- Language
- English
- Date published
- 08/2021
- Academic Unit
- Pathology
- Record Identifier
- 9984618644102771
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