Pharmacogenetics and Pharmacogenomics Eric Jorgenson 2/24/9

Outline Introduction Introduction Examples Examples Pharmacogenetics Pharmacogenetics Pharmacogenomics Pharmacogenomics Environment and Drug Response Environment and Drug Response Additional Resources Additional Resources

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

Events in Pharmacogenetics Meyer Nature Reviews Genetics 2004

PTC and Pharmacogenetics Meyer Nature Reviews Genetics 2004

Bimodal Distribution of PTC Non-RespondersRespondersNo ToxicityToxicity

Diplotype and PTC Score Kim et al. Science 2003

Adapted from Bufe et al. Current Biology 2005

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

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

Drug transport, targeting, and metabolism

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

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

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

Outline Introduction Introduction Examples Examples Pharmacogenetics Pharmacogenetics Pharmacogenomics Pharmacogenomics Environment and Drug Response Environment and Drug Response Additional Resources Additional Resources

Phillips et al. JAMA 2001

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

TPMT and 6-mercaptopurine

Pharmacogenetics of TPMT

TPMT Haplotypes and Activity

Standard TPMT Dosing

Drug Exposure and Toxicity

Genotype Specific TPMT Dosing

Drug Exposure and Toxicity

Pharmacogenetics of Acetylation Weinshilboum NEJM 2003

NAT2 and Race/Ethnicity

Pharmacogenetics of CYP2D6 Weinshilboum NEJM 2003

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

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

CYP2D6 and Race/Ethnicity

Pharmacogenetics and Race/Ethnicity Weinshilboum NEJM 2003

Drug Metabolism and ADRs

Outline Introduction Introduction Examples Examples Pharmacogenetics Pharmacogenetics Pharmacogenomics Pharmacogenomics Environment and Drug Response Environment and Drug Response Additional Resources Additional Resources

Pharmacogenetics and Pharmacogenomics

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

Pharmacogenomics Evans and Relling Nature 2004

Genome-wide Association and Drug Response GWAS Catalog: GWAS Catalog: Nicotine Dependence Nicotine Dependence Long QT Syndrome Long QT Syndrome Statin-induced Myopathy Statin-induced Myopathy

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

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

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

Manhattan Plot of GWAS SEARCH Consortium NEJM 2008

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

Myopathy attributable to rs within patients on 80mg of Simvastatin SEARCH Consortium NEJM 2008

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

Outline Introduction Introduction Examples Examples Pharmacogenetics Pharmacogenetics Pharmacogenomics Pharmacogenomics Environment and Drug Response Environment and Drug Response Additional Resources Additional Resources

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

Drug levels Dahan and Altman EJCN 2004

Grapefruit juice drug interactions Dahan and Altman EJCN 2004

Outline Introduction Introduction Examples Examples Pharmacogenetics Pharmacogenetics Pharmacogenomics Pharmacogenomics Environment and Drug Response Environment and Drug Response Additional Resources Additional Resources

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

More on Pharmacogenetics Pharmacogenetics Knowledge Base (PharmGKB) Pharmacogenetics Knowledge Base (PharmGKB)PharmGKB

More Examples Evans and Mcleod NEJM 2003

Even more Examples Evans and Mcleod NEJM 2003