Journal article
Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity
Clinical pharmacology and therapeutics, Vol.102(4), pp.662-670
10/2017
DOI: 10.1002/cpt.685
PMCID: PMC6138243
PMID: 28295243
Abstract
Dihydropyrimidine dehydrogenase (DPD;
DPYD
gene) variants have emerged as reliable predictors of adverse toxicity to the chemotherapy agent 5-fluorouracil (5-FU). The intronic
DPYD
variant rs75017182 has been recently suggested to promote alternative splicing of
DPYD
. However, both the extent of alternative splicing and the true contribution of rs75017182 to DPD function remain unclear. In the present study we quantified alternative splicing and DPD enzyme activity in rs75017182 carriers utilizing healthy volunteer specimens from the Mayo Clinic Biobank. Although the alternatively spliced transcript was uniquely detected in rs75017182 carriers, canonically spliced
DPYD
levels were only reduced by 30% (
p
=2.8×10
−6
) relative to controls. Similarly, DPD enzyme function was reduced by 35% (
p
=0.025). Carriers of the well-studied toxicity-associated variant rs67376798 displayed similar reductions in DPD activity (31% reduction). The modest effects on splicing and function suggest that rs75017182 may have clinical utility as a predictor of 5-FU toxicity similar to rs67376798.
Details
- Title: Subtitle
- Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity
- Creators
- Qian Nie - Mayo ClinicShikshya Shrestha - Mayo ClinicErin E. Tapper - Mayo ClinicColbren S. Trogstad-Isaacson - University of MinnesotaKelly J. Bouchonville - Mayo ClinicAdam M. Lee - University of MinnesotaRentian Wu - Mayo ClinicCalvin R. Jerde - Mayo ClinicZhiquan Wang - University of MinnesotaPhillip A. Kubica - Mayo ClinicSteven M. Offer - Mayo ClinicRobert B. Diasio - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Clinical pharmacology and therapeutics, Vol.102(4), pp.662-670
- DOI
- 10.1002/cpt.685
- PMID
- 28295243
- PMCID
- PMC6138243
- NLM abbreviation
- Clin Pharmacol Ther
- ISSN
- 0009-9236
- eISSN
- 1532-6535
- Grant note
- name: Mayo Clinic Cancer Center, award: CA15083
- Language
- English
- Date published
- 10/2017
- Academic Unit
- Pathology
- Record Identifier
- 9984618510502771
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