Pharmacogenetics to predict drug-related adverse events.
Identification of reliable markers to predict drug-related adverse events (DRAEs) is an important goal of the pharmaceutical industry and others within the healthcare community. We have used genetic polymorphisms, including the most frequent source of variation (single nucleotide polymorphisms, SNPs) in the human genome, in pharmacogenetic approaches designed to predict DRAEs. Three studies exemplify the principles of using polymorphisms to identify associations in progressively larger genomic regions: polymorphic repeats within the UDP-glucuronysltransferase I (UGT1A1) gene in patients experiencing hyperbilirubinemia after administration of tranilast, an experimental drug to prevent re-stenosis following coronary revascularization; high linkage disequilibrium within the Apolipoprotein E (ApoE) gene in patients with Alzheimer Disease (AD); and the polymorphic variant HLA-B57 in patients with hypersensitivity reaction after administration of abacavir, a nucleoside reverse transcriptase inhibitor for the treatment of HIV. Together, these studies demonstrate in a stepwise manner the feasibility of using pharmacogenetic approaches to predict DRAEs.
Hosford
David A
DA
Department of Genetics Research, GlaxoSmithKline R&D, Research Triangle Park, North Carolina 27709, USA. david.hosford@gsk.com
Lai
Eric H
EH
Riley
John H
JH
Xu
Chun-Fang
CF
Danoff
Theodore M
TM
Roses
Allen D
AD
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D015224:Dideoxynucleosides / Q000627:therapeutic use; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D015810:Linkage Disequilibrium; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D062367:ortho-Aminobenzoates / Q000627:therapeutic use; D000099227:Abacavir
D001057:Apolipoproteins E; D015224:Dideoxynucleosides; D014453:Glucuronosyltransferase; D062367:ortho-Aminobenzoates; D000099227:Abacavir; C012293:tranilast