Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene.

Kuilenburg, André B P van; Meijer, Judith; Tanck, Michael W T; Dobritzsch, Doreen; Zoetekouw, Lida; Dekkers, Lois-Lee; Roelofsen, Jeroen; Meinsma, Rutger; Wymenga, Machteld; Kulik, Wim; Büchel, Barbara; Hennekam, Raoul C M; Largiadèr, Carlo Rodolfo (2016). Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene. Biochimica et biophysica acta - molecular basis of disease, 1862(4), pp. 754-762. Elsevier 10.1016/j.bbadis.2016.01.009

[img] Text
1-s2.0-S0925443916000107-main.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-associated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905+1G>A) and the combined presence of three risk variants in DPYD (c.1905+1G>A, c.1129-5923C>G, c.2846A>T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the novel p.G401R mutation is most likely minor. The clinical relevance of the p.D949V mutation was demonstrated in a cancer patient heterozygous for the c.2846A>T mutation and a novel nonsense mutation c.1681C>T (p.R561X), experiencing severe grade IV toxicity. Our studies showed that the endogenous levels of uracil and the U/UH2 ratio are poor predictors of an impaired DPD activity. Loading studies with uracil to identify patients with a DPD deficiency warrants further investigation.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Büchel, Barbara and Largiadèr, Carlo Rodolfo


600 Technology > 610 Medicine & health








Marie-Christine Müller

Date Deposited:

04 Jun 2018 11:15

Last Modified:

25 Oct 2019 13:40

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

5-Fluorouracil DPYD Dihydropyrimidine dehydrogenase Pharmacogenetics Pyrimidine metabolism




Actions (login required)

Edit item Edit item
Provide Feedback