title: Sequencing drug response with HapMap.
abstract: The information about how DNA sequence varies across the human genome is crucial for unravelling the genetic basis of drug response. A haplotype map, or HapMap, intended to reveal such a variation pattern, has been recently developed by the International HapMap Consortium. Here, we present a conceptual model for directly characterizing specific DNA sequence variants that are responsible for drug response based on the haplotype structure provided by HapMap. Our model is developed in the maximum likelihood context, incorporated by clinically meaningful mathematical functions that model drug response and implemented with the EM algorithm. Our model is employed to a pharmacogenetic study of cardiovascular disease with 107 patients. We found that the haplotype constituted by allele Gly16 (G) at codon 16 and allele Glu27 (G) at codon 27 genotyped within the beta2AR candidate gene exhibits a different effect on heart rate curve from the rest haplotypes. Parents with the diplotype consisting of two copies of haplotype GG are more sensitive in heart rate to increasing dosages of dobutamine than those with other haplotypes. This model provides a powerful tool for elucidating the genetic variants of drug response and ultimately designing personalized medications based on each patient's genetic constitution.
authors.affiliation: Department of Statistics, University of Florida, Gainesville, FL 32611, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: C
authors.initials: C
authors.lastname: Aquilante
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Wu
mesh_terms: D000465:Algorithms; D000483:Alleles; D002316:Cardiotonic Agents / Q000494:pharmacology; D002874:Chromosome Mapping; D003198:Computer Simulation; D004280:Dobutamine / Q000494:pharmacology; D005787:Gene Frequency; D006239:Haplotypes; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D008957:Models, Genetic; D010597:Pharmacogenetics / Q000295:instrumentation*; D010600:Pharmacology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000295:instrumentation*
chemical_list: D002316:Cardiotonic Agents; D004280:Dobutamine