In Silico Analysis of the Diversity of DPYD Gene Variants Aff ecti ng Fluoropyrimidine Toxicity: A Comparison of South Asians with Other World Populati ons

Abstract

Fluoropyrimidine (FP) chemotherapy drug is uti lized to treat colon, head, neck and breast cancers. Apart from its eff ecti veness, toxicity is a limitati on. DPD (dihydropyrimidine dehydrogenase) enzyme, which aids in the FP metabolism is produced by the highly polymorphic DPYD gene. Mutati ons in the DPYD gene cause the defi ciency or non-functi onality of the DPD enzyme which varies among diff erent populati ons. This research aimed to compare allele frequencies of common DPYD gene variants of South Asians (SAS) such as DPYD*2A(rs3918290), DPYD*9(rs1801265), DPYD*5, rs2297595, DPYD*6, rs17376848, rs56038477, DPYD*4(rs1801158), rs67376798 and rs75017182 with Africans (AFR), Amish (AMI), Lati n Americans (AMR), Ashkenazi Jewish (ASJ), East Asians (EAS), Finnish (FIN) and Non-Finnish (NFE). Allele frequencies were obtained from the Genome Aggregati on Database in the PharmGKB database. Χ² analysis was performed. p<0.05 was deemed to be stati sti cally signifi cant. The study found a signifi cant diff erence between the SAS populati on and AFR, AMR, ASJ, EAS, FIN and NFE populati ons for the DPYD*9A gene variant, except for the AMI populati on. The distributi on of the DPYD*2A gene variant of SAS was found to be signifi cant in the AFR, ASJ, FIN and NFE populati ons, except for AMR and AMI. The prevalence of DPYD*5, DPYD*6, rs17376848, and rs56038477 in the SAS signifi cantly diff ered from all above-menti oned populati ons. The distributi on of the rs75017182 gene variant in SAS has shown signifi cant diff erences with AFR, AMR, ASJ and EAS except for NFE and FIN. This study highlights the variati ons in pharmacogenomics data specifi c to populati ons that could lead to personalized medicine and the need for DPYD genotyping before cancer treatment, especially in SAS communiti es where clinically signifi cant geneti c variati ons and haplotypes occur. Study fi ndings pinpoint the potenti al contributi on of DPYD gene variati ons to individual variability in anti -cancer dosage requirements among SAS.