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Pharmacogenomics

Pharmacogenomics. Eric Jorgenson. Outline. Introduction Pharmacogenetics TPMT CYP2D6 Pharmacogenomics GWAS Gene Expression. What is Pharmacogenetics?. The study of the role of inheritance in the individual variation in drug response. Efficacy Toxicity.

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Pharmacogenomics

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  1. Pharmacogenomics Eric Jorgenson

  2. Outline • Introduction • Pharmacogenetics • TPMT • CYP2D6 • Pharmacogenomics • GWAS • Gene Expression

  3. What is Pharmacogenetics? • The study of the role of inheritance in the individual variation in drug response. • Efficacy • Toxicity

  4. Adverse Drug Reactions are common Phillips et al. JAMA 2001

  5. Events in Pharmacogenetics Meyer Nature Reviews Genetics 2004

  6. PTC and Pharmacogenetics Meyer Nature Reviews Genetics 2004

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

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

  9. Adapted from Bufe et al. Current Biology 2005

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

  11. Drug transport, targeting, and metabolism

  12. Pharmacodynamics • How a drug acts • Drug target

  13. Pharmacokinetics • How a drug is processed • ADME • Absorption • Distribution • Metabolism • Excretion • Drug Levels (dosage) • Efficacy • Toxicity

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

  15. Outline • Introduction • Pharmacogenetics • TPMT • CYP2D6 • Pharmacogenomics • GWAS • Gene Expression

  16. TPMT and 6-mercaptopurine

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

  18. Pharmacogenetics of TPMT

  19. TPMT Haplotypes and Activity

  20. Standard TPMT Dosing

  21. Drug Exposure and Toxicity

  22. Genotype Specific TPMT Dosing

  23. Drug Exposure and Toxicity

  24. More on TPMT • Pharmacogenetics Knowledge Base (PharmGKB) • http://www.PharmGKb.org

  25. Pharmacogenetics of CYP2D6 Weinshilboum NEJM 2003

  26. CYP2D6 Copy Number Variation Meyer Nature Reviews Genetics 2004

  27. Pharmacogenetics of Nortriptyline Weinshilboum NEJM 2003

  28. CYP2D6 and Race/Ethnicity

  29. Pharmacogenetics and Race/Ethnicity Weinshilboum NEJM 2003

  30. Drug Metabolism and ADRs

  31. GenotypePhenotype Studies • Survey genetic variation in genes of interest • Test genetic variants in laboratory studies • Recruit subjects with known variant genotypes • Pharmacogenomics of Membrane Transporters (PMT)

  32. Outline • Introduction • Pharmacogenetics • TPMT • CYP2D6 • Pharmacogenomics • GWAS • Gene Expression

  33. Pharmacogenetics and Pharmacogenomics

  34. What is Pharmacogenomics and how is it different from Pharmacogenetics? • Genomic scale • Array based platforms

  35. Pharmacogenomics Evans and Relling Nature 2004

  36. GWAS of Statin-Induced Myopathy

  37. Quantile-Quantile (QQ) Plot

  38. Manhattan Plot

  39. Odds ratios for rs4149056

  40. Cumulative risk of myopathy

  41. GWAS of Platelet Aggregation inResponse to Clopidogrel

  42. Platelet Aggregation inResponse to Clopidogrel Shuldiner et al. JAMA 2009

  43. Dubai Plot

  44. CYP2C19*2 modifies platelet aggregation in response to clopidogrel

  45. Event-free survival

  46. 3 GWAS of sustained virological response to PEGylated interferon- and ribavirin

  47. Manhattan Plot Tanaka et al. Nature Genetics 2009

  48. Variation in Il28B predicts Sustained Virological Response in Hepatitis C Ge Nature Genetics 2009

  49. Haplotype effects Supiah et al. Nature Genetics 2009

  50. GWAS of acenocoumarol mainenance dosage

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