title: DMET microarray technology for pharmacogenomics-based personalized medicine.
abstract: 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.
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA. burmester.jim@mcrf.mfldclin.edu
authors.forename: James K
authors.initials: JK
authors.lastname: Burmester
authors.forename: Marina
authors.initials: M
authors.lastname: Sedova
authors.forename: Michael H
authors.initials: MH
authors.lastname: Shapero
authors.forename: Elaine
authors.initials: E
authors.lastname: Mansfield
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D000077144:Clopidogrel; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism; D017743:Equipment Reuse; D005787:Gene Frequency; D016678:Genome / Q000235:genetics; D006801:Humans; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis / Q000295:instrumentation / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010597:Pharmacogenetics / Q000295:instrumentation / Q000379:methods*; D016133:Polymerase Chain Reaction; D057285:Precision Medicine / Q000295:instrumentation / Q000379:methods*; D013194:Staining and Labeling; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004798:Enzymes; D004364:Pharmaceutical Preparations; D014859:Warfarin; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D013988:Ticlopidine