The ABC s of Pharmacogenomics and Pharmacogenetics. Guillaume Pare MD, M.Sc., FRCPc Research Fellow Harvard Medical School

Transcription

1 The ABC s of Pharmacogenomics and Pharmacogenetics Guillaume Pare MD, M.Sc., FRCPc Research Fellow Harvard Medical School

2 Objectives Understand terms relating to pharmacogenomics and pharmacogenetics Understand basic concepts of pharmacogenomics and pharmacogenetics Provide some examples of advances in this field

3 Definitions Study of the contribution of inheritance to variation in the drug response phenotype Goal: To develop ways to maximize drug efficacy, minimize toxicity, and select responsive patients Pharmacogenetics Vs Pharmacogenomics

4 Pharmacogenetics Genetic variations can affect the concentration of a drug reaching it s target (pharmacokinetics) Liberation Absorption Distribution Metabolism Excretion Or can also occur in the drug target itself or in related signaling cascade (pharmacodynamics)

5 Pharmacogenetics and the Successes of (Mostly) Mendelian Genetics See Weinshilboum and Wang, Ann Rev Genomics Genet : for excellent review

6 Some History One of the earliest example by Kalow et al. in the 1950s Hydrolysis of succinylcholine by butyrylcholinesterase (BCHE, pseudocholinesterase ) Mostly the result of a single nonsynonymous coding single nucleotide polymorphism (Asp70>Gly) = homozygous for the atypical allele = heterozygous = homozygous for the common allele Adapted from Kalow W, Staron N. Can. J. Biochem. Physiol :

7 Is Drug Response Heritable? What is heritability? Proportion of phenotypic variation in a population that is attributable to genetic variation among individuals Estimated using data from closely related individuals - such as twins, sibs, parents and offspring Typically around 50% for complex traits

8 Is Drug Response Heritable? Plasma dicuramol and antipyrine half-life values Adapted from Vesell and Page. J. Clin. Invest : and Vesell and Page. Science : 72-3

9 Pharmacokinetic Genes Phase I metabolism Oxidation, reduction, hydrolysis, cyclization and decyclization Cytochrome P450 family, etc. Phase II metabolism Conjugation reactions UGT, TPMT, etc. Other: Absorption, distribution, excretion

10 Examples of FDA Approved PK Genetics Tests Gene Drug Consequence TPMT Mercaptopurine and azathiopurine Neutropenia UGT1A1 Irinotecan Neutropenia CYP2D6 Codeine derivatives Inadequate benefit

11 What about pharmacodynamics? How heritable are pharmacodynamics effects? Difficult to assess Few studies Heritability of platelet responsiveness to aspirin Platelet pathways directly related to COX-1 completely inhibited Residual activity in pathways indirectly related to COX-1 Post-ASA Heritability ranging from 27-76% for platelet activation indices indirectly related to COX-1 Faraday n. et al. Circ :

12 What about pharmacodynamics? Heart failure and -blockade -Blockade Catecholamine -Adrenergic Receptor GRK5 The Q41L variant of GRK5 Frequency of 25% in Af. Am. Increased GRK5 activity Not associated with heart failure But associated with improved survival in heart failure patients Increased Heart Failure Liggett SB et al. Nat. Med :

13 What about pharmacodynamics? Heart failure and -blockade (continued) GRK5 Q41 (Common allele) GRK5 L41 (Protective allele) Liggett SB et al. Nat. Med :

14 Warfarin Pharmacogenetics Most widely prescribed oral anticoagulant Predominantly metabolized by CYP2C9 CYP2C9*1: Reference allele CYP2C9*2 (Arg144Cys): 12% of reference activity (frq=8-12%) CYP2C9*3 (Ile358Leu): 5% of reference activity (frq=6-10%) Explains 6-10% of variance in Warfarin dose Rieder et al. NEJM :

15 Warfarin Pharmacogenetics The target of Warfarin is VKORC1, but no nonsynonymous coding variant observed Haplotype analysis reveals the importance of genetic variants of that gene Explains 25% of variance in Warfarin dose Rieder et al. NEJM :

16 Warfarin Pharmacogenetics Haplotype: A way of denoting the collective genotype of a number of closely linked loci on a chromosome SNP A SNP B SNP C

17 Warfarin Pharmacogenetics Rieder et al. NEJM :

18 Warfarin Pharmacogenetics Can it help estimate the appropriate dose of Warfarin? The International Warfarin Pharmacogenetics Consortium NEJM : Next step: Adverse events & drug efficacy

19 Pharmacogenomics and the Challenges of Complex Traits

20 Why Pharmacogenomics? Drug effects are complex, non-mendelian traits Genetic epidemiology shows that such inheritance pattern is compatible with a polygenic model of inheritance Need to study multiple genes at the time, or even whole genomes

21 Challenges

22 Challenges Genetic variations are expected to have small individual effects but nevertheless collectively result in marked familial clustering and high heritability (~50%) Multiple hypothesis testing Suppose a French Roulette with numbers 1 to 20 The probability of having a 1 is 0.05 But if we play the roulette 100K times, we would expect the ball to fall on the 1 5,000 times!! P-values must be corrected!! Population stratification Risk of confounding when genetically heterogeneous populations are analyzed together

23 Successful Translation: The Abacavir Example Abacavir hypersensitivity syndrome (AHS) is a potentially life-threatening illness occurring in 4-8% of those initiating the drug AHS was found to be associated with HLA-B*5701 with sensitivity >97% and specificity >99% Negative predictive value of 100% Positive predictive value of 47.9% Mallal. S. et al. Lancet : Hetherington S. et al. Lancet : Mallal S. et al. NEJM :

24 Successful Translation: The Abacavir Example Phillips EJ. Clin. Infect. Dis : 103-5

25 Successful Translation: The Abacavir Example Roses AD. Nat. Rev. Drug Disc :

26 Conclusion Genetic variation contributes to inter-individual differences in the drug response phenotype at every pharmacologic step Through individualized treatments, pharmacogenetics and pharmacogenomics are expected to lead to: Better, safer drugs the first time More accurate methods of determining appropriate drug dosages Pharmacogenomics offers unprecedented opportunities to understand the genetic architecture of drug response

27 Thanks!