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Using HapMap tools in pharmacogenomic discovery: the thiopurine methyltransferase polymorphism.
1Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, and College of Pharmacy, University of Tennessee, Memphis, TN, USA.
Clinical Pharmacology and Therapeutics
|March 3, 2007
Summary
The International HapMap Project aids pharmacogenetic discovery for drug response. While useful for known genes, identifying new drug-related genes using a genome-wide approach remains challenging.
Area of Science:
- Pharmacogenomics
- Genetics
- Drug Metabolism
Background:
- The International HapMap Project aims to identify genetic variations influencing drug response.
- The thiopurine methyltransferase (TPMT) 719A>G single-nucleotide polymorphism (SNP) is linked to reduced enzyme activity and increased drug toxicity.
- Pharmacogenetics seeks to understand how genes affect individual responses to drugs.
Purpose of the Study:
- To evaluate the utility of HapMap resources for identifying pharmacogenetic determinants of drug response.
- To determine if the TPMT 719A>G SNP can predict TPMT enzyme activity and phenotype.
- To assess the effectiveness of genome-wide versus candidate gene approaches in pharmacogenetic discovery.
Main Methods:
- Utilized HapMap cell lines and 3.3 million single-nucleotide polymorphisms (SNPs).
- Tested candidate gene association for the TPMT 719A>G SNP and its predictive power for TPMT phenotype.
- Employed a genome-wide approach to rank all genes based on their prediction of TPMT activity.
Main Results:
- Five SNPs and four haplotypes, including two in complete linkage disequilibrium with the functional TPMT 719A>G SNP, predicted TPMT phenotype when TPMT was a candidate gene.
- A TPMT haplotype (HAP1) significantly predicted TPMT phenotype.
- Genome-wide analysis revealed that haplotypes of 96 other genes ranked higher than TPMT in predicting TPMT activity.
Conclusions:
- HapMap resources are valuable for pharmacogenetic discovery when the target gene is already known.
- Challenges persist in definitively identifying novel genes associated with drug response using a genome-wide, agnostic approach.
- Further refinement of genome-wide strategies is needed for comprehensive pharmacogenetic discovery.
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