Interactions

Eric JorgensonEPI 2172/22/11

Outline

• Gene-Environment Interaction

• Gene-Gene Interaction

• Pharmacogenetics

• Pharmacogenomics

• Mental retardation and seizures• 1/15,000 live births

o 1/100,000 in Finlando 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

Strata Cases Controls

Gene (G+)Environment (E+)

a b

Gene (G+)No Environment (E-)

c d

No Gene (G-) Environment (E+)

e f

No Gene (G-) No Environment (E-)

g h

Gene-Environment Interaction

Gene-Environment Interaction

Strata Cases Controls

G+E+ a b

G+E- c d

G-E+ e f

G-E- g h

Odds Ratio (OR)

ah / bg

ch / dg

eh / fg

1

Multiplicative Effects

G+E+ 45 15G+E- 15 5G-E+ 9 3G-E- 3 1

Strata RiskAbsolute

Ratio Odds

Multiplicative Effects

OR Interaction = ORG+E+ / ORG+E- ORG-E+

If OR Interaction = 1, multiplicative effects

Example: OR Interaction = 15 / 5 x 3OR Interaction = 1

Factor V Leiden Mutations, Oral Contraceptive Use, and Venous Thrombosis

Strata Cases Controls

G+E+ 25 2

G+E- 10 4

G-E+ 84 63

G-E- 36 100

OR

34.7

6.9

3.7

Reference

Total 155 169Vanderbroucke 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+ 34.7

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

PTC Distribution

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Number of Subjects

Non-Responders

RespondersNo Toxicity Toxicity

Diplotype and PTC Score

0

2

4

6

8

10

12

14

16

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Raw PTC Score

Number of Subjects

PAV/PAV

PAV/AVI

AAV/AVI

AVI/AVI

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 toxicityo Rare diseases (need multiple affected family

members)

Pharmacodynamics

• How a drug acts

• Drug target

Pharmacokinetics

• How a drug is processed• ADME

o Absorptiono Distributiono Metabolismo Excretion

• Drug Levels (dosage)o Efficacyo Toxicity

Drug levels in the body

• Plasma concentration

• Metabolic Ratioo Compare blood vs. urineo Probe drugo Can be measured over time

TPMT and 6-mercaptopurine

Thiopurine S-methyltransferase (TPMT)

• Drugs:o 6-mercaptopurineo azathiopurine

• Diseases:o Acute lymphoblastic leukemiao Inflammatory bowel disease

• Toxicity:o Fatal myelosuppressiono 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)

• http://www.PharmGKb.org

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 rs4149056

Cumulative risk of myopathy

GWAS of Platelet Aggregation inResponse to Clopidogrel

Platelet Aggregation inResponse 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?