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Pharmacogenetics and Pharmacogenomics

Pharmacogenetics and Pharmacogenomics. Eric Jorgenson 2/24/9. Outline. Introduction Examples Pharmacogenetics Pharmacogenomics Environment and Drug Response Additional Resources. What is Pharmacogenetics?.

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Pharmacogenetics and Pharmacogenomics

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  1. Pharmacogenetics and Pharmacogenomics Eric Jorgenson 2/24/9

  2. Outline • Introduction • Examples • Pharmacogenetics • Pharmacogenomics • Environment and Drug Response • Additional Resources

  3. What is Pharmacogenetics? • The study of the role of inheritance in the individual variation in drug response. • How it differs from disease genetics • Gene-environment interaction • Can involve multiple gene-environment interactions • Ethical/Methodological constraints

  4. Events in Pharmacogenetics Meyer Nature Reviews Genetics 2004

  5. PTC and Pharmacogenetics Meyer Nature Reviews Genetics 2004

  6. Bimodal Distribution of PTC Non-Responders No Toxicity Responders Toxicity

  7. Diplotype and PTC Score Kim et al. Science 2003

  8. Adapted from Bufe et al. Current Biology 2005

  9. Pharmacogenetic Study Design • Family Studies • Linkage Analysis • Family and Linkage are difficult to do for some phenotypes: • Severe toxicity • Rare diseases (need multiple affected family members)

  10. Pharmacogenetic Study Design:Candidate Gene Studies • Phenotype-to-Genotype • Identify a drug response phenotype • Choose a candidate gene • Genotype-to-Phenotype • Identify genetic polymorphisms in a gene of interest • Choose study subjects with different genotypes • Give probe drug to subjects • Smaller sample size needed • Best for measuring pharmacokinetic response

  11. Drug transport, targeting, and metabolism

  12. Pharmacodynamics • What a drug does to the body • Usually refers to the interaction of the drug with the drug target • Pharmacogentics: Polymorphisms in the drug target

  13. Pharmacokinetics • How a drug is processed by the body • ADME • Absorption • Distribution • Metabolism • Excretion • Drug Levels • Efficacy • Toxicity

  14. Drug levels in the body • Plasma concentration • Therapeutic window • Metabolic Ratio • Compare blood vs. urine • Probe drug • Can be measured over time

  15. Outline • Introduction • Examples • Pharmacogenetics • Pharmacogenomics • Environment and Drug Response • Additional Resources

  16. Phillips et al. JAMA 2001

  17. Thiopurine S-methyltransferase (TPMT) • Drugs: • 6-mercaptopurine • azathiopurine • Diseases: • Acute lymphoblastic leukemia • Inflammatory bowel disease • Toxicity: • Fatal myelosuppression • Hematopoietic toxicity

  18. TPMT and 6-mercaptopurine

  19. Pharmacogenetics of TPMT

  20. TPMT Haplotypes and Activity

  21. Standard TPMT Dosing

  22. Drug Exposure and Toxicity

  23. Genotype Specific TPMT Dosing

  24. Drug Exposure and Toxicity

  25. Pharmacogenetics of Acetylation Weinshilboum NEJM 2003

  26. NAT2 and Race/Ethnicity

  27. Pharmacogenetics of CYP2D6 Weinshilboum NEJM 2003

  28. CYP2D6 Copy Number Polymorphism and Nortriptyline Metabolic Ratio Meyer Nature Reviews Genetics 2004

  29. Plasma Concentration of Nortriptyline vs. CYP2D6 Copy Number Weinshilboum NEJM 2003

  30. CYP2D6 and Race/Ethnicity

  31. Pharmacogenetics and Race/Ethnicity Weinshilboum NEJM 2003

  32. Drug Metabolism and ADRs

  33. Outline • Introduction • Examples • Pharmacogenetics • Pharmacogenomics • Environment and Drug Response • Additional Resources

  34. Pharmacogenetics and Pharmacogenomics

  35. What is Pharmacogenomics and how is it different from Pharmacogenetics? • Genomic scale • Array based platforms • DNA: genetic variation • RNA: gene expression • Protein: protein activity

  36. Pharmacogenomics Evans and Relling Nature 2004

  37. Genome-wide Association and Drug Response • GWAS Catalog: http://www.genome.gov/26525384 • Nicotine Dependence • Long QT Syndrome • Statin-induced Myopathy

  38. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) • Randomized Trial • 12,064 participants • Prior MI • Simvastatin: 80mg vs. 20mg • 6,031 on 80mg • 49 definite myopathy cases • 49 incipient myopathy cases SEARCH Consortium NEJM 2008

  39. Selection of subjects for genotyping • 96 cases on 80mg simvastatin • 48 definite myopathy • 48 incipient myopathy • 96 matched controls on 80mg simvastatin • Sex • Age • eGFR • Amiodarone use SEARCH Consortium NEJM 2008

  40. Subjects and Genotyping platform • 85 cases, 90 controls • 1 case dropped for non-European ancestry • Others dropped for lack of DNA • Illumina HumanHap300 • 318,237 SNPs • 316,184 SNPs passed QC SEARCH Consortium NEJM 2008

  41. Manhattan Plot of GWAS SEARCH Consortium NEJM 2008

  42. Replication (?) • Heart Protection Study • 40mg simvastatin vs. placebo • 40mg: 23 myopathy cases • Placebo: 9 myopathy cases • 16,664 genotyped participants • 21 cases • 16,643 controls • Relative Risk = 2.6 per allele • Compared to Odds Ratio = 4.4 per allele SEARCH Consortium NEJM 2008

  43. Myopathy attributable to rs4149056 within patients on 80mg of Simvastatin SEARCH Consortium NEJM 2008

  44. Gene Expression Diagnostic Test • Oncotype DX • Tests expression of 21 genes in tumor samples • Recurrence Score of 0-100 • Women with higher scores are more likely to benefit from chemotherapy

  45. Outline • Introduction • Examples • Pharmacogenetics • Pharmacogenomics • Environment and Drug Response • Additional Resources

  46. Pharmacoenvironment • Grapefruit juice-felodipine interaction • bergamottin inhibition of CYP3A4 in the small intestine

  47. Drug levels Dahan and Altman EJCN 2004

  48. Grapefruit juice drug interactions Dahan and Altman EJCN 2004

  49. Outline • Introduction • Examples • Pharmacogenetics • Pharmacogenomics • Environment and Drug Response • Additional Resources

  50. Reviews of Pharmacogenetics • Evans and Mcleod NEJM 2003 • Goldstein, Tate, Sisodiya Nature Reviews Genetics 2003 • Meyer Nature Reviews Genetics 2004 • Evans and Relling Nature 2004 • Wilkinson NEJM 2005

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