Analysis of the influence of rs1801265 polymorphism on DPD enzyme activity and contributing factors in the Chinese population.

INTRODUCTION

Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD, is essential for 5-fluorouracil (5-FU) metabolism, yet functional variants remain understudied in Chinese populations.

METHODS

We enrolled 300 healthy Chinese subjects and measured DPD activity as the HPLC-based 5-FU degradation rate in PBMCs. Five DPYD SNPs selected from NCBI and PharmGKB were genotyped by SNaPshot; genotype-degradation-rate associations were assessed by univariate and multivariable regression with FDR correction, and functional consequences predicted using PolyPhen-2, SIFT, SWISS-MODEL and molecular docking.

RESULTS

The median degradation rate was 1.140 ng/mL/106 cells/min. c.85T > C (rs1801265) was the only variant associated with a higher degradation rate (p = 0.0041) and remained independently associated in the multivariable model; it is common in Asians (MAF ~7%). In 39 colorectal cancer patients receiving 5-FU-based chemotherapy, carriers showed numerically lower 5-FU AUC and shorter progression-free survival, without statistical significance. Molecular modeling predicted that the Cys29Arg substitution alters DPD conformation and 5-FU binding.

CONCLUSION

DPYD c.85T > C (rs1801265) was associated with higher 5-FU degradation capacity in Chinese subjects and is predicted to increase DPD activity. If confirmed, this gain-of-function effect may reduce fluoropyrimidine toxicity but could also warrant dose escalation to maintain efficacy; direct functional assays and prospective patient-cohort validation are required before clinical use.