PHAT: The Pharmacogenetics of Asthma TreatmentChanning Laboratory, Brigham and Women’s Hospital and Harvard Medical School

University of Maryland School of MedicineWake Forest University School of Medicine

Our Team

Our Collaborators

Project Overview

ACKNOWLEDGEMENTSFunding: U01 HL65899 from the National Heart, Lung and Blood Institute, National Institutes of Health. We also wish to acknowledge the RIKEN/PGRN collaboration for its assistance in the GWAS genotyping of the LOCCS, LODO, and Sepracor populations.

Resources

Channing Laboratory

Brigham and Women’s Hospital

Harvard Medical School

Boston, MA

www.pharmgat.org

Principal Investigators

Scott T Weiss, M.D., M.S.

Kelan Tantisira, M.D., M.P.H

Investigative Staff

Augusto Litonjua, M.D., M.P.H., Beta-agonist and Vitamin D Association Studies

Jessica Lasky-Su, Sc.D. , Lead Statistician

Blanca Himes, Ph.D., Bayesian and Informatics Analyses

Ann Chen Wu, M.D., M.P.H., Population Pharmacogenomics

Angela Rogers, M.D., M.P.H., Integrative Pharmacogenomics, Copy Number Variants

Quan Lu, Ph.D., High Throughput siRNA Screening

Barbara Klanderman, Ph.D., Genetics Laboratory Director

Ross Lazarus, M.B.B.S., M.P.H., Bioinformatics Director

Jody Sylvia, Bioinformatics Manager

Qing Ling Duan, Ph.D., Post-Doctoral Fellow

Stephen B. Liggett, M.D., Principal Investigator

University of Maryland School of Medicine

Functional Genomics of the Beta-Agonist Pathway

Eugene R. Bleecker, M.D., Principal Investigator

Wake Forest University School of Medicine

Pharmacogenetic Association Replication Studies

• Asthma is a complex genetic disease, with heritability estimates as high as 0.75

• The treatment response to the three major classes of asthma medications is also heritable, based on twin studies, wide inter-individual variability (Figure), and high inter-individual repeatability

• Our project seeks to identify the genetic determinants of the variable response to inhaled corticosteroids and beta-agonist therapy in asthma, to functionally characterize these variants, and to formulate predictive models of response to asthma medications

Pat

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Adult StudyCAMPACRN

Figure 1: Lung function response to inhaled corticosteroid therapy in 3 populations

SPECIFIC AIM 1• GWAS Analysis of Pharmacogenetic Phenotypes• Replication Analyses in Clinical Trials and Cohorts

Weiss, Bleecker, Tantisira, Litonjua, Klanderman, Su, Himes, Wu

SPECIFIC AIM 2• Find functional variants

• mRNA• Integrative Genomics/Systems Biology• Cellular/Animal

• High Throughput Gene Sequencing

Klanderman, Tantisira, Su, Rogers,Liggett, Tamari, Lu

• Tantisira, Schadt, Nickle – integrative • Tamari - steroid pathway• Liggett - 2Agonist pathway• Klanderman, Tantisira - sequencing

SPECIFIC AIM 3• Develop Prognostic testing Weiss, Himes, Su, Wu, McGeahie

SPECIFIC AIM 4 • Communicate results to PharmGKB• Develop new statistical tools• Develop new bioinformatic tools

Sylvia, LitonjuaLange, Su, MurphySylvia, Ziniti, Carey, Meyers

SPECIFIC AIM 5 • Collaborate with PharmGKB investigators Weiss, Tantisira, Litonjua

SPECIFIC AIM 6• Enable asthma pharmacogenetics investigators Weiss, Bleecker, Israel, Lima

Aim 1 - Populations

Our Specific Aims

Aims 2 and 3 - Overview

• Informatics and Analytic Expertise:

• Family-based statistical analysis

• GWAS pipeline and analysis

• Integrative genomics

• Bayesian statistical approaches

• Cellular Resources:

• 705 immortalized lymphocytes from asthmatic probands

• Baseline and post-dexamethasone microarray data on 164

• Population Resources

• SHARP – archived on dbGAP

• Open for collaborations involving other clinical trial populations

• Emerging “real life” populations:

• Crimson – database and samples form deidentified Partners Health Care system subjects

• Harvard Pilgrim Health Care – large Boston-based health care insurer

• Partners Asthma Centers – population of referral asthmatics