title: Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity.
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.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Nie
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Tapper
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Trogstad-Isaacson
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Bouchonville
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Jerde
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Kubica
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Mayo Clinic College of Medicine, Mayo Clinic, 200 1st St. SW, Rochester, Minnesota, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Offer
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Mayo Clinic Cancer Center, Rochester, Minnesota, USA.|Mayo Clinic College of Medicine, Mayo Clinic, 200 1st St. SW, Rochester, Minnesota, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Diasio
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil