1. PHAT: The Pharmacogenetics of Asthma Treatment Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School University of Maryland School of Medicine Wake Forest University School of Medicine Our Team Our Collaborators Project Overview ACKNOWLEDGEMENTS Funding: 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 Patients, % % Change in FEV 1 from Baseline 0 5 10 15 20 25 30 35 40 < -20 -20 to -10 -10 to 0 0 to 10 10 to 2020 to 3030 to 40 > 40 Adult Study CAMP ACRN Figure 1: Lung function response to inhaled corticosteroid therapy in 3 populations 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