Interactions Eric Jorgenson EPI 217 2/22/11

Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

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

Phenylalanine Metabolism

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

PKU: Gene-Environment Interaction

Gene-Environment Interaction

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

Multiplicative Effects G+E G+E G-E+ 9 3 G-E- 3 1 StrataRisk Absolute Ratio Odds

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

Factor V Leiden Mutations, Oral Contraceptive Use, and Venous Thrombosis OR Reference Total Vanderbroucke et al. The Lancet 1994

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

Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

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

GWAS of Psoriasis Strange et al. Nature Genetics 2010

Gene-Gene Interaction Strange et al. Nature Genetics 2010

Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

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

Phillips et al. JAMA 2001 Adverse Drug Reactions are common

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 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)

Pharmacodynamics How a drug acts Drug target

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

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

TPMT and 6-mercaptopurine

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

Pharmacogenetics of TPMT

TPMT Haplotypes and Activity

Standard TPMT Dosing

Drug Exposure and Toxicity

Genotype Specific TPMT Dosing

Drug Exposure and Toxicity

More on TPMT Pharmacogenetics Knowledge Base (PharmGKB)PharmGKB

Pharmacogenetics of CYP2D6 Weinshilboum NEJM 2003

Meyer Nature Reviews Genetics 2004 CYP2D6 Copy Number Variation

Pharmacogenetics of Nortriptyline Weinshilboum NEJM 2003

CYP2D6 and Race/Ethnicity

Pharmacogenetics and Race/Ethnicity Weinshilboum NEJM 2003

Drug Metabolism and ADRs

Outline Gene-Environment Interaction Gene-Gene Interaction Pharmacogenetics Pharmacogenomics

Pharmacogenetics and Pharmacogenomics

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

Pharmacogenomics Evans and Relling Nature 2004

GWAS of Statin-Induced Myopathy

Quantile-Quantile (QQ) Plot

Manhattan Plot

Odds ratios for rs

Cumulative risk of myopathy

GWAS of Platelet Aggregation in Response to Clopidogrel

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

Dubai Plot

CYP2C19*2 modifies platelet aggregation in response to clopidogrel

Event-free survival

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

Manhattan Plot Tanaka et al. Nature Genetics 2009

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

Haplotype effects Supiah et al. Nature Genetics 2009

GWAS of acenocoumarol mainenance dosage

Acenocoumarol maintenance dosage Teichert et al. Human Molecular Genetics 2009

Acenocoumarol maintenance dosage adjusted for top SNPs

Acenocumarol dosage variance explained

ROC Curves Attia et al. JAMA 2009

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?