1. Interactions Eric Jorgenson EPI 217 2/22/11

2. Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

3. Mental retardation and seizures 1/15,000 live births o 1/100,000 in Finland o 1/2,600 in Turkey PKU: Phenylketonuria

4. Phenylalanine Metabolism

5. PKU: Phenylketonuria Causes Mutations in Phenylalanine Hydroxylase (PAH) Dietary Phenylalanine Both are necessary Neither is sufficient

6. PKU: Gene-Environment Interaction

7. Gene-Environment Interaction

8. Odds Ratio (OR) ah / bg ch / dg eh / fg 1

9. Multiplicative Effects G+E+ 4515 G+E- 15 5 G-E+ 9 3 G-E- 3 1 StrataRisk Absolute Ratio Odds

10. Multiplicative Effects OR Interaction = OR G+E+ / OR G+E- OR G-E+ If OR Interaction = 1, multiplicative effects Example: OR Interaction = 15 / 5 x 3 OR Interaction = 1

11. Factor V Leiden Mutations, Oral Contraceptive Use, and Venous Thrombosis OR 34.7 6.9 3.7 Reference Total 155 169 Vanderbroucke et al. The Lancet 1994

12. Evidence for G-E Interaction OR Interaction = 34.7 / 6.9 x 3.7 = 1.4 Strata OR G+E+ 34.7 G+E- 6.9 G-E+ 3.7 G-E- Ref

13. Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

14. Gene-Gene Interaction Models Marchini et al. Nature Genetics 2005

15. GWAS of Psoriasis Strange et al. Nature Genetics 2010

16. Gene-Gene Interaction Strange et al. Nature Genetics 2010

17. Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

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

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

20. PTC and Pharmacogenetics Meyer Nature Reviews Genetics 2004

21. Bimodal Distribution of PTC Non-RespondersRespondersNo ToxicityToxicity

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

23. Adapted from Bufe et al. Current Biology 2005

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

25. Pharmacodynamics How a drug acts Drug target

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

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

28. TPMT and 6-mercaptopurine

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

30. Pharmacogenetics of TPMT

31. TPMT Haplotypes and Activity

32. Standard TPMT Dosing

33. Drug Exposure and Toxicity

34. Genotype Specific TPMT Dosing

35. Drug Exposure and Toxicity

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

37. Pharmacogenetics of CYP2D6 Weinshilboum NEJM 2003

38. Meyer Nature Reviews Genetics 2004 CYP2D6 Copy Number Variation

39. Pharmacogenetics of Nortriptyline Weinshilboum NEJM 2003

40. CYP2D6 and Race/Ethnicity

41. Pharmacogenetics and Race/Ethnicity Weinshilboum NEJM 2003

42. Drug Metabolism and ADRs

43. Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

44. Pharmacogenetics and Pharmacogenomics

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

46. Pharmacogenomics Evans and Relling Nature 2004

47. GWAS of Statin-Induced Myopathy

48. Quantile-Quantile (QQ) Plot

49. Manhattan Plot

50. Odds ratios for rs4149056

51. Cumulative risk of myopathy

52. GWAS of Platelet Aggregation in Response to Clopidogrel

53. Platelet Aggregation in Response to Clopidogrel Shuldiner et al. JAMA 2009

54. Dubai Plot

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

56. Event-free survival

57. 3 GWAS of sustained virological response to PEGylated interferon-  and ribavirin

58. Manhattan Plot Tanaka et al. Nature Genetics 2009

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

60. Haplotype effects Supiah et al. Nature Genetics 2009

61. GWAS of acenocoumarol mainenance dosage

62. Acenocoumarol maintenance dosage Teichert et al. Human Molecular Genetics 2009

63. Acenocoumarol maintenance dosage adjusted for top SNPs

64. Acenocumarol dosage variance explained

65. ROC Curves Attia et al. JAMA 2009

66. Challenges for Pharmacogenomics How predictive is a test? Does the test apply to all groups? Is a test superior to current clinical practice? Will testing improve outcomes? Is testing cost effective?