Screening of Dihydropyrimidine Dehydrogenase Genetic Variants by Direct Sequencing in Different Ethnic Groups

Abstract

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.

Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients

“…Different populations and races show different prevalence of IVS14 + 1G > A polymorphism in the DPYD [29]. In a study on 72 patients in Taiwan, 2.7% of patients had IVS14 + 1G > A polymorphism in the DPYD [30].…”

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

“…Similarly, the Dutch Pharmacogenetics Working Group (DPWG) guidelines define these same four variants as risk factors for FP-related toxicity and recommend reducing treatment dosage when a patient possesses one of them [47]. Although DPYD*9A, *5, and *6 are common variants in many ethnic groups, these four risk variants have not yet been identified in Asians [48][49][50].…”

Determination of DPYD Enzyme Activity in Korean Population

“…Our previous study, as well as Cho et al, reported on DPYD genetic variants in Koreans. 15,16 Sohn et al 17 also examined DPYD activity in a Korean population. To date, however, association between DPYD genetic variants and their enzyme activity in Koreans has not been reported.…”

“…In this study, as a follow-up to our previous study, 15 we directly sequenced DPYD and determined its enzyme activity in 73 Korean subjects. Further association analysis between DPYD genetic variants and enzyme activity was also conducted based on the genotype of each genetic variant.…”