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Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity
Q Nie1, S Shrestha1, E E Tapper1
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
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.
Insights
Genetic variants in the Dihydropyrimidine dehydrogenase (DPD) gene, like rs75017182, impact 5-fluorouracil (5-FU) chemotherapy toxicity. This study found rs75017182 modestly affects DPD splicing and function, suggesting clinical utility for predicting patient response.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Clinical Chemistry
Background:
- Dihydropyrimidine dehydrogenase (DPD) activity is crucial for metabolizing 5-fluorouracil (5-FU), a widely used chemotherapy agent.
- Genetic variants in the DPYD gene, encoding DPD, are known predictors of 5-FU toxicity.
- The intronic DPYD variant rs75017182 has been proposed to influence DPYD alternative splicing, but its functional impact is not well-defined.
Purpose of the Study:
- To quantify the extent of alternative splicing caused by the DPYD variant rs75017182.
- To assess the impact of rs75017182 on DPD enzyme activity.
- To compare the functional effects of rs75017182 with a known DPYD toxicity variant, rs67376798.
Main Methods:
- Analysis of alternative splicing and DPD enzyme activity in healthy volunteers carrying the rs75017182 variant.
- Utilized specimens from the Mayo Clinic Biobank.
- Quantified DPYD transcript levels and enzyme function.
Main Results:
- The alternatively spliced DPYD transcript was exclusively found in rs75017182 carriers.
- Canonical DPYD levels were reduced by approximately 30% in carriers (P = 2.8 × 10-6).
- DPD enzyme activity showed a 35% reduction in carriers (P = 0.025), comparable to the 31% reduction observed in carriers of the known toxicity variant rs67376798.
Conclusions:
- The DPYD variant rs75017182 leads to modest but significant reductions in DPYD splicing and enzyme activity.
- These functional changes are similar in magnitude to those caused by the well-established DPYD toxicity variant rs67376798.
- Rs75017182 holds potential clinical utility for predicting 5-FU chemotherapy toxicity.
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