DMET™ Microarray Technology for Pharmacogenomics-Based Personalized Medicine

  • James K. BurmesterEmail author
  • Marina Sedova
  • Michael H. Shapero
  • Elaine Mansfield
Part of the Methods in Molecular Biology book series (MIMB, volume 632)


Human genome sequence variation in the form of single nucleotide polymorphisms (SNPs) as well as more complex structural variation such as insertions, duplications, and deletions underlies each individual’s response to drugs and thus the likelihood of experiencing an adverse drug reaction. The ongoing challenge of the field of pharmacogenetics is to further understand the relationship between genetic variation and differential drug responses, with the overarching goal being that this will lead to improvements in both the safety and efficacy of drugs. The Affymetrix® DMET™ Plus Premier Pack (DMET stands for Drug Metabolizing Enzymes and Transporters) enables highly multiplexed genotyping of known polymorphisms in Absorption, Distribution, Metabolism, and Elimination (ADME)-related genes on a single array. The DMET Plus Panel interrogates markers in 225 genes that have documented functional significance in phase I and phase II drug metabolism enzymes as well as drug transporters. The power of the DMET Assay has previously been demonstrated with regard to several different drugs including warfarin and clopidogrel. In a research study using an earlier four-color version of the assay, it was demonstrated that warfarin dosing can be influenced by a cytochrome P450 (CYP) 4F2 variant. Additionally, the assay has been used to demonstrate that CYP2C19 variants with decreased enzyme activity led to lower levels of the active clopidogrel metabolite, resulting in a decreased inhibition of platelets and a higher rate of cardiovascular events when compared to noncarriers of the DNA variant. Thus, highly multiplexed SNP genotyping focused on ADME-related polymorphisms should enable research into development of safer drugs with greater efficacy.

Key words

ADME Clopidogrel DMET (drug metabolizing enzymes and transporters) Genetic testing SNP genotyping Warfarin 



The authors thank Marshfield Clinic Research Foundation for its support through the assistance of Amy VanProosdy and Alice Stargardt in the preparation of this chapter.


  1. 1.
    Thacker SM, Grice GR, Milligan PE, Gage BF (2008) Dosing anticoagulant therapy with coumarin drugs: is genotyping clinically useful? Yes. J Thromb Haemost 6:1445-1449PubMedCrossRefGoogle Scholar
  2. 2.
    Huang RS, Ratain MJ (2009) Pharmaco­genetics and pharmacogenomics of anticancer agents. CA Cancer J Clin 59:42-55PubMedCrossRefGoogle Scholar
  3. 3.
    Singh SS (2006) Preclinical pharmacokinetics: an approach towards safer and efficacious drugs. Curr Drug Metab 7:165-182PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshizawa M, Hayashi H, Tashiro Y et al (2009) Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients. Thromb Res 124:161-166PubMedCrossRefGoogle Scholar
  5. 5.
    Kang JS, Lee MH (2009) Overview of therapeutic drug monitoring. Korean J Intern Med 24:1-10PubMedCrossRefGoogle Scholar
  6. 6.
    Hamdy SI, Hiratsuka M, Narahara K et al (2002) Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol 53:596-603PubMedCrossRefGoogle Scholar
  7. 7.
    Mizutani T (2003) PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev 35:99-106PubMedCrossRefGoogle Scholar
  8. 8.
    Nakai K, Tsuboi J, Okabayashi H et al (2007) Ethnic differences in the VKORC1 gene polymorphism and an association with warfarin dosage requirements in cardiovascular surgery patients. Pharmacogenomics 8:713-719PubMedCrossRefGoogle Scholar
  9. 9.
    Wilke RA, Lin DW, Roden DM et al (2007) Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6:904-916PubMedCrossRefGoogle Scholar
  10. 10.
    Flockhart DA, Tanus-Santos JE (2002) Implications of cytochrome P450 interactions when prescribing medication for hypertension. Arch Intern Med 162:405-412PubMedCrossRefGoogle Scholar
  11. 11.
    Bosch TM, Meijerman I, Beijnen JH, Schellens JH (2006) Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clin Pharmacokinet 45:253-285PubMedCrossRefGoogle Scholar
  12. 12.
    Lacaná E, Amur S, Mummanneni P, Zhao H, Frueh FW (2007) The emerging role of pharmacogenomics in biologics. Clin Pharmacol Ther 82:466-471PubMedCrossRefGoogle Scholar
  13. 13.
    Frueh FW, Gurwitz D (2004) From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community. Pharmacogenomics 5:571-579PubMedCrossRefGoogle Scholar
  14. 14.
    Frueh FW, Amur S, Mummaneni P et al (2008) Pharmacogenomic biomarker information in drug labels approved by the United States food and drug administration: prevalence of related drug use. Pharmacotherapy 28:992-998PubMedCrossRefGoogle Scholar
  15. 15.
    Daly TM, Dumaual CM, Miao X et al (2007) Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport. Clin Chem 53:1222-1230PubMedCrossRefGoogle Scholar
  16. 16.
    Dumaual C, Miao X, Daly TM et al (2007) Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System. Pharmacogenomics 8:293-305PubMedCrossRefGoogle Scholar
  17. 17.
    Caldwell MD, Awad T, Johnson JA et al (2008) CYP4F2 genetic variant alters required warfarin dose. Blood 111:4106-4112PubMedCrossRefGoogle Scholar
  18. 18.
    Brandt JT, Close SL, Iturria SJ et al (2007) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5:2429-2436PubMedCrossRefGoogle Scholar
  19. 19.
    Hardenbol P, Banér J, Jain M et al (2003) Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat Biotechnol 21:673-678PubMedCrossRefGoogle Scholar
  20. 20.
    Hardenbol P, Yu F, Belmont J et al (2005) Highly multiplexed molecular inversion probe genotyping: over 10, 000 targeted SNPs geno­typed in a single tube assay. Genome Res 15:269-275PubMedCrossRefGoogle Scholar
  21. 21.
    Robarge JD, Li L, Desta Z, Nguyen A, Flockhart DA (2007) The star-allele nomenclature: retooling for translational genomics. Clin Pharmacol Ther 82:244-248PubMedCrossRefGoogle Scholar
  22. 22.
    Borgiani P, Ciccacci C, Forte V et al (2009) CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics 10:261-266PubMedCrossRefGoogle Scholar
  23. 23.
    Cooper GM, Johnson JA, Langaee TY et al (2008) A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 112:1022-1027PubMedCrossRefGoogle Scholar
  24. 24.
    Perez-Andreu V, Roldan V, Anton AI et al (2009) Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood 113:4977-4979PubMedCrossRefGoogle Scholar
  25. 25.
    McDonald MG, Rieder MJ, Nakano M, Hsia CH, Rettie AE (2009) CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol 75:1337-1346PubMedCrossRefGoogle Scholar
  26. 26.
    Takeuchi F, McGinnis R, Bourgeois S et al (2009) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 5:e1000433PubMedCrossRefGoogle Scholar
  27. 27.
    Mega JL, Close SL, Wiviott SD et al (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354-362PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • James K. Burmester
    • 1
    Email author
  • Marina Sedova
    • 2
  • Michael H. Shapero
    • 2
  • Elaine Mansfield
    • 3
  1. 1.Center for Human GeneticsMarshfield Clinic Research FoundationMarshfieldUSA
  2. 2.Assay and Application Product DevelopmentAffymetrix, IncSanta ClaraUSA
  3. 3.Application Sciences DepartmentAffymetrix, Inc.Santa ClaraUSA

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