Identification of a pharmacogenetic effect by linkage disequilibrium mapping.
A practical limitation to the identification of genetic profiles predictive of drug-induced adverse events is the number of patients with the adverse event that can be tolerated before the drug is withdrawn. Whole genome screening for regions of linkage disequilibrium (LD) associated with a particular phenotype may provide the mechanism to rapidly discover specific and sensitive profiles. We have used data from a large phase III clinical trial of tranilast and typed 76 SNPs over a 2.7 megabase region flanking the uridine diphosphate glucuronosyltranserferase 1A1 gene. Three SNPs within one LD block showed strong association with tranilast-induced hyperbilirubinemia (P<10(-13)). Our data illustrated that a genome-wide LD scan of 100,000-200,000 SNPs is sufficient to identify a pharmacogenetic association with a drug-induced adverse event.
Discovery and Pipeline Genetics, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK. cfx74267@gsk.com
C-F
CF
Xu
K F
KF
Lewis
A J
AJ
Yeo
L C
LC
McCarthy
M F
MF
Maguire
Z
Z
Anwar
T M
TM
Danoff
A D
AD
Roses
I J
IJ
Purvis
D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D062367:ortho-Aminobenzoates / Q000627:therapeutic use; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D062367:ortho-Aminobenzoates; D000099148:UGT1A1 Enzyme; C012293:tranilast