Pharmacogenetics and Pharmacogenomics

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