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Licensed Unlicensed Requires Authentication Published by De Gruyter March 20, 2015

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

  • Ann K. Daly EMAIL logo


Data on frequency of pharmacogenetic polymorphisms in the UK population are limited. However, availability of whole genome sequencing data on 94 UK controls of European ethnicity from the 1000 genomes project together with similar data on other populations provides a valuable new source of data in this area and allows direct comparison of allele frequencies with those for other European populations. The ethnic diversity of the UK population also needs to be considered, and 1000 genomes includes data on South Asians, the most common ethnic group in the UK after White Europeans. Allele frequencies for polymorphisms in genes relevant to phase I and phase II drug metabolism for UK, Finnish, Spanish and South Asian populations were obtained from the literature and 1000 genomes. Generally there was good agreement between the literature and 1000 genomes reports. CYP2D6*4, the most common CYP2D6 poor metabolizer allele among Europeans, appears more common in the UK than in Spain and Finland, whereas, as suggested previously, CYP2C19*2 and CYP2C9*2 appear more common in Finland and Spain, respectively, than in the UK. South Asians show low frequencies of CYP2C9*2 and CYP2C19*17 but higher frequencies of CYP2C19*2 compared with UK residents of European ethnicity. Though personalizing drug treatment on the basis of individual genotype rather than ethnicity may be more appropriate, differences in allele frequencies across continents should be considered when designing clinical trials of new drugs.

Corresponding author: Professor Ann K. Daly, Institute of Cellular Medicine, Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK, E-mail:


1. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature 2010;467:1061–73.10.1038/nature09534Search in Google Scholar

2. Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, et al. Genes mirror geography within Europe. Nature 2008;456:98–101.10.1038/nature07331Search in Google Scholar

3. Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 2014;46:1173–86.10.1038/ng.3097Search in Google Scholar

4. Bernal ML, Sinues B, Johansson I, McLellan RA, Wennerholm A, Dahl ML, et al. Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics 1999;9:657–60.10.1097/00008571-199910000-00013Search in Google Scholar

5. Auton A, Bryc K, Boyko AR, Lohmueller KE, Novembre J, Reynolds A, et al. Global distribution of genomic diversity underscores rich complex history of continental human populations. Genome Res 2009;19:795–803.10.1101/gr.088898.108Search in Google Scholar

6. Agundez JA, Martinez C, Ledesma MC, Ladona MG, Ladero JM, Benitez J. Genetic basis for differences in debrisoquine polymorphism between a Spanish and other white populations. Clin Pharmacol Ther 1994;55:412–7.10.1038/clpt.1994.50Search in Google Scholar

7. Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Agundez JA. High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 2001;57:47–9.10.1007/s002280100264Search in Google Scholar

8. Sistonen J, Fuselli S, Palo JU, Chauhan N, Padh H, Sajantila A. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics 2009;19:170–9.10.1097/FPC.0b013e32831ebb30Search in Google Scholar

9. Evans DA, White TA. Human acetylation polymorphism. J Lab Clin Med 1964;63:394–403.Search in Google Scholar

10. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977;2:584–6.10.1016/S0140-6736(77)91430-1Search in Google Scholar

11. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990;347:773–6.10.1038/347773a0Search in Google Scholar PubMed

12. Hanioka N, Kimura S, Meyer UA, Gonzalez FJ. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934 – a base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3’ splice recognition site. Am J Hum Genet 1990;47:994–1001.Search in Google Scholar

13. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 1990;265:17209–14.10.1016/S0021-9258(17)44890-3Search in Google Scholar

14. Blum M, Demierre A, Grant DM, Heim M, Meyer UA. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc Natl Acad Sci USA 1991;88:5237–41.10.1073/pnas.88.12.5237Search in Google Scholar

15. de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994;269:15419–22.10.1016/S0021-9258(17)40694-6Search in Google Scholar

16. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996;6:341–9.10.1097/00008571-199608000-00007Search in Google Scholar

17. Llerena A, Cobaleda J, Benitez J. Debrisoquine hydroxylation phenotypes in healthy volunteers. Lancet 1989;1:1398.10.1016/S0140-6736(89)92854-7Search in Google Scholar

18. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312–8.10.1200/JCO.2005.03.3266Search in Google Scholar

19. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:704.10.1016/S0140-6736(06)69255-6Search in Google Scholar

20. Furuta T, Shirai N, Takashima M, Xiao F, Hanai H, Sugimura H, et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 2001;69:158–68.10.1067/mcp.2001.113959Search in Google Scholar

21. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010;121:512–8.10.1161/CIRCULATIONAHA.109.885194Search in Google Scholar

22. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353:717–9.10.1016/S0140-6736(98)04474-2Search in Google Scholar

23. Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, et al. Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003;76:1233–5.10.1097/01.TP.0000090753.99170.89Search in Google Scholar

24. Azuma J, Ohno M, Kubota R, Yokota S, Nagai T, Tsuyuguchi K, et al. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy. Eur J Clin Pharmacol 2013;69:1091–101.10.1007/s00228-012-1429-9Search in Google Scholar

25. Lennard L. Implementation of TPMT testing. Br J Clin Pharmacol 2014;77:704–14.10.1111/bcp.12226Search in Google Scholar

26. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007;132:272–81.10.1053/j.gastro.2006.11.023Search in Google Scholar

27. Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH, et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 2003;73:566–74.10.1016/S0009-9236(03)00053-5Search in Google Scholar

28. Daly AK. Pharmacogenetics and human genetic polymorphisms. Biochem J 2010;429:435–49.10.1042/BJ20100522Search in Google Scholar PubMed

29. Daly AK. Genetic polymorphisms affecting drug metabolism: recent advances and clinical aspects. Adv Pharmacol 2012;63:137–67.10.1016/B978-0-12-398339-8.00004-5Search in Google Scholar PubMed

30. Sim SC, Kacevska M, Ingelman-Sundberg M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J 2013;13:1–11.10.1038/tpj.2012.45Search in Google Scholar PubMed

31. Daly AK, Armstrong M, Monkman SC, Idle ME, Idle JR. Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes. Pharmacogenetics 1991;1:33–41.10.1097/00008571-199110000-00006Search in Google Scholar PubMed

32. Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997;60:284–95.Search in Google Scholar

33. Daly AK, Leathart JB, London SJ, Idle JR. An inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitution. Hum Genet 1995;95:337–41.10.1007/BF00225204Search in Google Scholar PubMed

34. Beyeler C, Armstrong M, Bird HA, Idle JR, Daly AK. Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 1996;55:66–8.10.1136/ard.55.1.66Search in Google Scholar PubMed PubMed Central

35. Roddam PL, Rollinson S, Kane E, Roman E, Moorman A, Cartwright R, et al. Poor metabolizers at the cytochrome P450 2D6 and 2C19 loci are at increased risk of developing adult acute leukaemia. Pharmacogenetics 2000;10:605–15.10.1097/00008571-200010000-00004Search in Google Scholar PubMed

36. Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996;6:429–39.10.1097/00008571-199610000-00007Search in Google Scholar PubMed

37. Jorgensen AL, Al-Zubiedi S, Zhang JE, Keniry A, Hanson A, Hughes DA, et al. Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics 2009;19:800–12.10.1097/FPC.0b013e3283317ab5Search in Google Scholar PubMed PubMed Central

38. King BP, Leathart JB, Mutch E, Williams FM, Daly AK. CYP3A5 phenotype-genotype correlations in a British population. Br J Clin Pharmacol 2003;55:625–9.10.1046/j.1365-2125.2003.01798.xSearch in Google Scholar PubMed PubMed Central

39. Risch A, Wallace DM, Bathers S, Sim E. Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet 1995;4:231–6.10.1093/hmg/4.2.231Search in Google Scholar PubMed

40. Agundez JA, Olivera M, Martinez C, Ladero JM, Benitez J. Identification and prevalence study of 17 allelic variants of the human NAT2 gene in a white population. Pharmacogenetics 1996;6:423–8.10.1097/00008571-199610000-00006Search in Google Scholar

41. Ng CS, Hasnat A, Al Maruf A, Ahmed MU, Pirmohamed M, Day CP, et al. N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group. Eur J Clin Pharmacol 2014;70:1079–86.10.1007/s00228-014-1703-0Search in Google Scholar PubMed

42. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999;9:37–42.10.1097/00008571-199902000-00006Search in Google Scholar PubMed

43. LLerena A, Naranjo ME, Rodrigues-Soares F, Penas LE, Farinas H, Tarazona-Santos E. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metab Toxicol 2014;10:1569–83.10.1517/17425255.2014.964204Search in Google Scholar PubMed

44. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006;79:103–13.10.1016/j.clpt.2005.10.002Search in Google Scholar

45. Nahar R, Deb R, Saxena R, Puri RD, Verma IC. Variability in CYP2C9 allele frequency: a pilot study of its predicted impact on warfarin response among healthy South and North Indians. Pharmacol Rep 2013;65:187–94.10.1016/S1734-1140(13)70977-0Search in Google Scholar

46. Elens L, van Gelder T, Hesselink DA, Haufroid V, van Schaik RH. CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics 2013;14:47–62.10.2217/pgs.12.187Search in Google Scholar

47. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 1996;347:578–81.10.1016/S0140-6736(96)91273-8Search in Google Scholar

48. Thibaudeau J, Lepine J, Tojcic J, Duguay Y, Pelletier G, Plante M, et al. Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone. Cancer Res 2006;66:125–33.10.1158/0008-5472.CAN-05-2857Search in Google Scholar PubMed

49. Hu DG, Meech R, Lu L, McKinnon RA, Mackenzie PI. Polymorphisms and haplotypes of the UDP-glucuronosyltransferase 2B7 gene promoter. Drug Metab Dispos 2014;42:854–62.10.1124/dmd.113.056630Search in Google Scholar PubMed

50. Nunes JM, Buhler S, Roessli D, Sanchez-Mazas A. The HLA-net GENE[RATE] pipeline for effective HLA data analysis and its application to 145 population samples from Europe and neighbouring areas. Tissue Antigens 2014;83:307–23.10.1111/tan.12356Search in Google Scholar PubMed

51. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol 2013;149:1025–32.10.1001/jamadermatol.2013.4114Search in Google Scholar PubMed

52. Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 2011;141:338–47.10.1053/j.gastro.2011.04.001Search in Google Scholar PubMed PubMed Central

53. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL, Jr, Tran E, Berger R, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther 2013;94:324–8.10.1038/clpt.2013.103Search in Google Scholar PubMed PubMed Central

54. Chen Z, Liew D, Kwan P. Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions. Neurology 2014;83:2077–84.10.1212/WNL.0000000000001034Search in Google Scholar PubMed

Received: 2014-11-6
Accepted: 2015-1-23
Published Online: 2015-3-20
Published in Print: 2015-9-1

©2015 by De Gruyter

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