dc.creator | Hamzic S., Schärer D., Offer S.M., Meulendijks D., Nakas C., Diasio R.B., Fontana S., Wehrli M., Schürch S., Amstutz U., Largiadèr C.R. | en |
dc.date.accessioned | 2023-01-31T08:27:47Z | |
dc.date.available | 2023-01-31T08:27:47Z | |
dc.date.issued | 2021 | |
dc.identifier | 10.1111/bcp.14742 | |
dc.identifier.issn | 03065251 | |
dc.identifier.uri | http://hdl.handle.net/11615/73879 | |
dc.description.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. © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | en |
dc.language.iso | en | en |
dc.source | British Journal of Clinical Pharmacology | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85103396393&doi=10.1111%2fbcp.14742&partnerID=40&md5=e98cb90164b825e21ae79a0a5305217b | |
dc.subject | dihydropyrimidine dehydrogenase | en |
dc.subject | dihydrouracil | en |
dc.subject | fluorouracil | en |
dc.subject | uracil | en |
dc.subject | dihydropyrimidine dehydrogenase | en |
dc.subject | fluorouracil | en |
dc.subject | adult | en |
dc.subject | Article | en |
dc.subject | blood level | en |
dc.subject | cancer chemotherapy | en |
dc.subject | cancer patient | en |
dc.subject | cohort analysis | en |
dc.subject | controlled study | en |
dc.subject | disease marker | en |
dc.subject | enzyme activity | en |
dc.subject | female | en |
dc.subject | gene frequency | en |
dc.subject | gene linkage disequilibrium | en |
dc.subject | genetic risk | en |
dc.subject | genetic variability | en |
dc.subject | genotype | en |
dc.subject | haplotype | en |
dc.subject | human | en |
dc.subject | major clinical study | en |
dc.subject | male | en |
dc.subject | malignant neoplasm | en |
dc.subject | middle aged | en |
dc.subject | reference value | en |
dc.subject | single nucleotide polymorphism | en |
dc.subject | adverse drug reaction | en |
dc.subject | genetics | en |
dc.subject | haplotype | en |
dc.subject | Dihydrouracil Dehydrogenase (NADP) | en |
dc.subject | Drug-Related Side Effects and Adverse Reactions | en |
dc.subject | Fluorouracil | en |
dc.subject | Genotype | en |
dc.subject | Haplotypes | en |
dc.subject | Humans | en |
dc.subject | John Wiley and Sons Inc | en |
dc.title | 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 | en |
dc.type | journalArticle | en |