Surveillance trials suggest that the risk for life-threatening asthma exacerbations are increased by a commonly prescribed class of inhaled beta2-adrenergic receptor agonists (beta agonists), the long-acting ?2-adrenergic receptor agonists (LABA).1-3 In contrast, prospective randomized trials demonstrated that LABA effectively control asthma when combined with an inhaled corticosteroid (ICS).30-32 A common, coding single nucleotide polymorphism (SNP) in the ?2-adrenergic receptor gene (ADRB2), Gly16Arg, modulates response to albuterol, a short-acting beta agonist (SABA), but not LABA.3-18 Adverse responses to LABA are rare and differ in frequency between ethnic groups, thus, pharmacogenetic studies based on rare variants (allele frequency < 0.05) or genetic ancestry are needed to address the LABA safety issue and identify mechanisms underlying differences in LABA response between African Americans and non-Hispanic Whites.1,3,22-26 We recently reported a study of rare ADRB2 variants demonstrating that non-Hispanic White asthmatics with the Ile164 variant and African Americans with a rare insertion (-376 In-Del) had an increased risk for severe exacerbations during LABA treatment.33 I also evaluated 191 African Americans from the NHLBI Severe Asthma Research Program (SARP) with whole-exome sequencing data to identify novel rare loci associated with beta agonist response.34 The goal of this proposal is to test the hypothesis that differential responses to inhaled beta agonists among asthmatics from different ethnic groups is determined by rare genetic variation within ADRB2, receptor signaling pathway genes, and additional loci throughout the genome. We propose three specific aims to test my hypothesis.
Aim 1 : To validate the effects of rare variants within ADRB2 and the ?2-adrenergic receptor (?2AR) signaling pathway on response to beta agonist therapy. We have genotyped 1,263 subjects from SARP and 377 subjects from Asthma Clinical Research Network trials (ACRN) with the Illumina HumanExome BeadChip (Exome Chip). Rare ADRB2 variants will be genotyped in 1,614 non-Hispanic Whites; 1,207 African Americans from three LABA-ICS clinical trials, including an ongoing NHLBI AsthmaNet trial; and 500 African Americans from an R01 of asthma severity. These 1,707 African Americans will be genotyped with the Illumina African Diaspora Power Chip (Diaspora Chip). These chips cover rare variants and will constitute studies to validate the effects of rare variants in ADRB2 and pathway genes on LABA response in asthmatics.
Aim 2 : To assess the effects of African ancestry and genetic variants co-inherited with African ancestry on the response to beta agonists in African American asthmatics. I will use SNPs from GWAS arrays, including the Diaspora Chip, for admixture-based approaches in African Americans from these asthma cohorts. I will evaluate the effect of global African ancestry on healthcare utilization and lung function during treatment with LABA or SABA and perform admixture mapping with fine mapping to identify loci associated with beta agonist response.
Aim 3 : To identify novel loci with rare variants associated with response to beta agonists in different ethnic asthma cohorts. I will integrate genotyping chip and sequencing data for whole-genome methods to identify novel loci with rare variants associated with beta agonist responsiveness in these multi-ethnic asthma cohorts. These genetic studies could define the small, important subgroup of asthmatics susceptible to severe, adverse effects of LABA therapy while elucidating the genetic basis for inter-ethnic differences in LABA responsiveness.1,22,27,28 Genetic variants from these studies could constitute genetic profiles for personalized approaches for the management of asthma in different ethnic groups.29 This research project will be complemented by graduate coursework in Molecular Medicine that will lead to a PhD including Molecular Genetics and Genomics of Human Disease (MCB 742), Clinical trials methods (CPTS 742), two genetic analytical course at the Cold Springs Harbor Laboratory, and one analytical course at the University of Alabama. This multi-faceted career development plan will occur in the context of the world-class mentoring and rigorous clinical trials experience available to me at the Wake Forest School of Medicine Center for Genomics and Personalized Medicine Research, site for NHLBI AsthmaNet and SARP, (Drs. ER Bleecker, SP Peters, and DA Meyers) and through outside collaboration with experts from National Jewish Health (Dr. ME Wechsler) and Johns Hopkins University (Dr. K Barnes). This plan will ultimately provide the experience and training which I require to reach my short-term goals of expertise in the design and ethical implementation of clinical trials, statistical and functional genomics, and the pharmacogenetics of complex lung disease. This plan will also set me on a path towards my long-term goal of independence as a physician-scientist in the fields of statistical and functional genomics. This application includes letters of support from: 1) Sally E. Wenzel, MD; University of Pittsburgh; 2) William W. Busse, MD; University of Wisconsin School of Medicine; 3) Esteban Gonzalez Burchard, MD, MPH; University of California, San Francisco; 4) Elliot Israel, MD; Brigham and Women's Hospital; 5) Stephan Lazarus, MD; University of California, San Francisco.
Surveillance trials suggest that the risk for life-threatening asthma exacerbations are increased with the use of a commonly prescribed class of inhaled beta2-adrenergic receptor agonist bronchodilators (beta agonists), the long-acting 2-adrenergic receptor agonists (LABA). This is an important public health issue 1-3 which has resulted in a safety review by the Food and Drug Administration resulting in a boxed warning and a mandated study of 46,800 patients with asthma to study LABA post-marketing safety which is in ongoing.3,19-21 Due to rarity of these adverse responses and the differences in response to LABA between ethnic groups, we propose genetic studies based on rare variants or genetic ancestry to address the LABA safety issue and identify why African Americans and non-Hispanic Whites respond differently to beta agonists in this three-year K08 proposal which provides training in clinical trials and pharmacogenetic studies.1,3,22-26
