Pharmacogenomics: The Promise of Personalized Medicine,Christina Aquilante, Pharm.D. Assistant Professor Department of Pharmaceutical Sciences School of Pharmacy University of Colorado at Denver and Health Sciences Center,Objectives,Provide an overview of pharmacogenomics and its clinical relevance Discuss clinically-relevant examples of: Drug metabolism pharmacogenomics Drug target pharmacogenomics Discuss the challenges facing pharmacogenomic studies and the movement of pharmacogenomics into clinical practice Discuss pharmacogenomics from the FDA and pharmaceutical industry perspective,Interindividual Variability in Drug Response,Disease Drug Class Rate of Poor Response Asthma Beta-agonists 40-75% Hypertension Various 30% Solid Cancers Various 70% Depression SSRIs, tricyclics 20-40% Diabetes Sulfonylureas, others 50% Arthritis NSAIDs, COX-2 inhibitors 30-60% Schizophrenia Various 25-75%,Factors Contributing to Interindividual Variability in Drug Disposition and Action,Age Race/ethnicity Weight Gender Concomitant Diseases Concomitant Drugs Social factors GENETICS,PERSONALIZED MEDICINE,“We wish to suggest a structure for the salt of DNA. This structure has novel features which are of considerable biological interest.”,Human Genome Project,Determine the sequence of the 3 billion nucleotides that make up human DNA Characterize variability in the genome Identify all the genes in human DNA The Era of Genomic Medicine: Improve prediction of drug efficacy or toxicity Improve the diagnosis of disease Earlier detection of genetic predisposition to disease,Newsweek June 25, 2001,“pharmacogenetics promises to target treatment to a patients genetic profile”,Genetics or Genomics?,Pharmacogenetics Study of how genetic differences in a SINGLE gene influence variability in drug response (i.e., efficacy and toxicity) Pharmacogenomics Study of how genetic (genome) differences in MULTIPLE genes influence variability in drug response (i.e., efficacy and toxicity),Current Concept of Pharmacogenomics,Roden DM et al. Ann Intern Med 2006; 145:749-57,Potential of Pharmacogenomics,Clinical Relevance,Can we predict who will derive an optimal response? Can we predict who will have a toxicity? Host (patient) genotype determines optimal drug therapy approach Disease (pathogen) genotype determines optimal drug therapy approach,DNA is Information,DNA A, T, G, C Codon Gene Chromosome Genome,ENGLISH Abcdefg.xyz Word Sentence Chapter Book,Composition of the Human Genome,Mutation/Polymorphism 1 bp Unit of genetic code 3 bp Coding sequence (exons) 3,000 bp Gene (exons and introns) 50,000 bp Chromosome 150,000,000 bp Human genome 3,000,000,000 bp,The Foundation of Pharmacogenomics: Differences in the Genetic Code Between People,Mutation: difference in the DNA code that occurs in less than 1% of population Often associated with rare diseases Cystic fibrosis, sickle cell anemia, Huntingtons disease Polymorphism: difference in the DNA code that occurs in more than 1% of the population A single polymorphism is less likely to be the main cause of a disease Polymorphisms often have no visible clinical impact,Single Nucleotide Polymorphisms (SNP),Pronounced “snip” Single base pair difference in the DNA sequence Over 2 million SNPs in the human genome Other polymorphisms: Insertion/deletion polymorphisms Gene duplications Gene deletions,Consequences of Polymorphisms,May result in a different amino acid or stop codon May result in a change in protein function or quantity May alter stability of mRNA No consequence,Genetics Terminology,Alleles = different DNA sequences at a locus Codon 389 1-AR Arg (0.75) Gly (0.25),Genotype = pair of alleles a person has at a region of the chromosome Codon 389 1-AR Arg389Arg Arg389Gly Gly389Gly,Genetics Terminology,Phenotype: outward manifestation of a trait Linkage: measure of proximity of 2 or more polymorphisms on a single chromosome Polymorphisms in close proximity tend to be co-inherited Regions of linked polymorphisms are known as haplotypes,Haplotype Map,For specific locations in the genome, a small number of SNP patterns (haplotypes) can account for 80-90% of entire human population International HapMap Project: Identifying common haplotypes in four populations from different parts of the world Identifying “tag” SNPs that uniquely identify these haplotypes,Pharmacogenomics,DRUG TARGETS,DRUG METABOLIZING ENZYMES,DRUG TRANSPORTERS,PHARMACOKINETICS,PHARMACODYNAMICS,Variability in Efficacy/Toxicity,Johnson JA. Trends in Genetics 2003: 660-666,Drug Metabolism Pharmacogenomics,Evidence of an inherited basis for drug response dates back in the literature to the 1950s Succinylcholine: 1 in 3000 patients developed prolonged muscle relaxation Monogenic Phenotype to genotype approach,Drug Metabolizing Enzymes,Examples of Drug Metabolism Pharmacogenomics,NEJM 2003; 348: 529-537,Examples of Drug Metabolism Pharmacogenomics,NEJM 2003; 348: 529-537,Warfarin and CYP2C9,Widely prescribed anticoagulant dr