J Korean Med Sci.  2013 Aug;28(8):1129-1133. 10.3346/jkms.2013.28.8.1129.

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

Affiliations
  • 1Department of Life Science, Sogang University, Seoul, Korea. hdshin@sogang.ac.kr
  • 2Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Korea.
  • 3Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Osong, Korea.
  • 4Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Osong, Korea.

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.

Keyword

Ethnic Gropus; Pharmacogenetics; Dihydropyrimidine Dehydrogenase; Fluorouracil

MeSH Terms

African Americans/genetics
Alleles
Amino Acids/metabolism
Asian Continental Ancestry Group/genetics
Dihydrouracil Dehydrogenase (NADP)/*genetics
Ethnic Groups/*genetics
European Continental Ancestry Group/genetics
Fluorouracil/metabolism
Gene Frequency
Genotype
Humans
Polymorphism, Single Nucleotide
Sequence Analysis, DNA
Amino Acids
Dihydrouracil Dehydrogenase (NADP)
Fluorouracil

Reference

1. Savonarola A, Palmirotta R, Guadagni F, Silvestris F. Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy. Pharmacogenomics J. 2012; 12:277–286.
2. Kristyanto H, Utomo AR. Pharmacogenetic application in personalized cancer treatment. Acta Med Indones. 2010; 42:109–115.
3. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989; 16:215–237.
4. Milano G, McLeod HL. Can dihydropyrimidine dehydrogenase impact 5-fluorouracil-based treatment? Eur J Cancer. 2000; 36:37–42.
5. Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011; 12:1321–1336.
6. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003; 3:330–338.
7. Mattison LK, Soong R, Diasio RB. Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics. Pharmacogenomics. 2002; 3:485–492.
8. Cerić T, Obralić N, Kapur-Pojskić L, Macić D, Beslija S, Pasić A, Cerić S. Investigation of IVS14 + 1G > A polymorphism of DPYD gene in a group of Bosnian patients treated with 5-Fluorouracil and capecitabine. Bosn J Basic Med Sci. 2010; 10:133–139.
9. Ezzeldin HH, Lee AM, Mattison LK, Diasio RB. Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients. Clin Cancer Res. 2005; 11:8699–8705.
10. Johnson MR, Wang K, Diasio RB. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin Cancer Res. 2002; 8:768–774.
11. Van Kuilenburg AB, Dobritzsch D, Meinsma R, Haasjes J, Waterham HR, Nowaczyk MJ, Maropoulos GD, Hein G, Kalhoff H, Kirk JM, et al. Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. Biochem J. 2002; 364:157–163.
12. Van Kuilenburg AB, Vreken P, Beex LV, Meinsma R, Van Lenthe H, De Abreu RA, van Gennip AH. Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity. Eur J Cancer. 1997; 33:2258–2264.
13. Ezzeldin H, Johnson MR, Okamoto Y, Diasio R. Denaturing high performance liquid chromatography analysis of the DPYD gene in patients with lethal 5-fluorouracil toxicity. Clin Cancer Res. 2003; 9:3021–3028.
14. Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer. 2004; 4:181–189.
15. Thompson D, Stram D, Goldgar D, Witte JS. Haplotype tagging single nucleotide polymorphisms and association studies. Hum Hered. 2003; 56:48–55.
16. Thorn CF, Marsh S, Carrillo MW, McLeod HL, Klein TE, Altman RB. PharmGKB summary: fluoropyrimidine pathways. Pharmacogenet Genomics. 2011; 21:237–242.
17. McLeod HL, Collie-Duguid ES, Vreken P, Johnson MR, Wei X, Sapone A, Diasio RB, Fernandez-Salguero P, van Kuilenberg AB, van Gennip AH, et al. Nomenclature for human DPYD alleles. Pharmacogenetics. 1998; 8:455–459.
18. Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol. 2007; 60:503–507.
19. Van Kuilenburg AB, Vreken P, Abeling NG, Bakker HD, Meinsma R, Van Lenthe H, De Abreu RA, Smeitink JA, Kayserili H, Apak MY, et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet. 1999; 104:1–9.
20. Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH. Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum Genet. 1997; 101:333–338.
21. Kelemen LE, Goodman MT, McGuire V, Rossing MA, Webb PM, Köbel M, Anton-Culver H, Beesley J, Berchuck A, Brar S, et al. Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev. 2010; 19:1822–1830.
22. Maekawa K, Saeki M, Saito Y, Ozawa S, Kurose K, Kaniwa N, Kawamoto M, Kamatani N, Kato K, Hamaguchi T, et al. Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences. J Hum Genet. 2007; 52:804–819.
23. Collie-Duguid ES, Etienne MC, Milano G, McLeod HL. Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics. 2000; 10:217–223.
24. Cho HJ, Park YS, Kang WK, Kim JW, Lee SY. Thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) polymorphisms in the Korean population for prediction of 5-fluorouracil-associated toxicity. Ther Drug Monit. 2007; 29:190–196.
25. Zhang H, Li YM, Zhang H, Jin X. DPYD*5 gene mutation contributes to the reduced DPYD enzyme activity and chemotherapeutic toxicity of 5-FU: results from genotyping study on 75 gastric carcinoma and colon carcinoma patients. Med Oncol. 2007; 24:251–258.
26. Yamaguchi K, Arai Y, Kanda Y, Akagi K. Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-Fluorouracil. Jpn J Cancer Res. 2001; 92:337–342.
27. Amstutz U, Farese S, Aebi S, Largiadèr CR. Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment. Pharmacogenomics. 2009; 10:931–944.
28. Savva-Bordalo J, Ramalho-Carvalho J, Pinheiro M, Costa VL, Rodrigues A, Dias PC, Veiga I, Machado M, Teixeira MR, Henrique R, et al. Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients. BMC Cancer. 2010; 10:470.
29. Yaman I, Fernandez J, Liu H, Caprara M, Komar AA, Koromilas AE, Zhou L, Snider MD, Scheuner D, Kaufman RJ, et al. The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader. Cell. 2003; 113:519–531.
30. Hellen CU, Sarnow P. Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev. 2001; 15:1593–1612.
31. Stoneley M, Willis AE. Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression. Oncogene. 2004; 23:3200–3207.
32. Chatterjee S, Pal JK. Role of 5'- and 3'-untranslated regions of mRNAs in human diseases. Biol Cell. 2009; 101:251–262.
33. Conklin D, Jonassen I, Aasland R, Taylor WR. Association of nucleotide patterns with gene function classes: application to human 3' untranslated sequences. Bioinformatics. 2002; 18:182–189.
34. Hirota T, Date Y, Nishibatake Y, Takane H, Fukuoka Y, Taniguchi Y, Burioka N, Shimizu E, Nakamura H, Otsubo K, et al. Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues. Lung Cancer. 2012; 77:16–23.
35. Ambros V. The functions of animal microRNAs. Nature. 2004; 431:350–355.
36. Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside. Nat Rev Drug Discov. 2004; 3:739–748.
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