Asthma affects 5% of the world population. In the U.S., asthma death rates are four-fold higher in Latinos and African Americans compared to Whites. Childhood asthma is a complex disease historically defined by partially overlapping clinical features. However, the heterogeneity observed in clinical disease and airway pathology suggests that the standard definition of asthma is composed of multiple clinical subgroups each with a distinct pathogenesis (i.e. endotypes). Gene expression profiling of bronchial airway brushings identified the type 2- high asthma endotype, defined by excessive airway inflammation driven by type 2 cytokines. We found that the type 2-high asthma endotype can be identified by gene expression profiling of minimally invasive nasal airway epithelium brushings. We also found high nasal expression of the type 2 cytokine, IL-13, was associated with higher risk of asthma attacks among Puerto Ricans, who have the highest asthma morbidity and mortality in the U.S. The populations with the highest asthma morbidity also have the poorest response to the most common asthma medication, albuterol. We hypothesize that specific molecular airway endotypes will define children with severe asthma and poor drug response and that these endotypes will have a strong genetic basis. To investigate this hypothesis the following aims are proposed: (1) Determine the expression endotypes of childhood asthma that underlie poor albuterol drug response and severe disease, using minimally invasive samples. Molecular endotyping with be performed by computational analysis of whole transcriptome sequencing data generated from 745 asthmatic and healthy children. Correlates of airway endotypes will be identified using peripheral blood gene expression. (2) Determine how IL-13 modifies airway cell responses to albuterol and HRV infection, and the genetic control of these responses. A powerful in vitro airway epithelial model will be used to determine if type 2 inflammation of the airway epithelium modifies transcriptional response to albuterol (most common asthma medication) and human rhinovirus (HRV) infection (most common trigger of asthma attacks). (3) Determine the genetic basis of and validate poor drug response and severe asthma endotypes in ethnically diverse children. We will perform the first genetic screen of type 2-high and other asthma endotypes. We will examine data from 4,379 minority children with asthma to determine how asthma endotypes influence response to albuterol and risk for severe asthma. Our goal is to understand the genetic basis of racial/ethnic differences in asthma severity and lung function. Results from this proposal will inform public health policy and clinical practice and aide in the mechanistic understanding of asthma severity (morbidity), which may lead to more targeted therapies. Data generated from our proposal will become a valuable resource for the medical and scientific communities.

Public Health Relevance

Although all people with asthma exhibit some degree of airway obstruction and respiratory symptoms, the clinical severity of their disease and response to common asthma medications varies greatly. We will use genetic and genomic analyses of nasal airway epithelial brushings from children with asthma to identify the pathobiological mechanisms (endotypes) that underlie severe asthma disease and poor response to albuterol. Results from this study will inform clinical practice and therapeutic decisions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135156-02
Application #
9477763
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Noel, Patricia
Project Start
2017-05-01
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Seibold, Max A (2018) Interleukin-13 Stimulation Reveals the Cellular and Functional Plasticity of the Airway Epithelium. Ann Am Thorac Soc 15:S98-S102
Gour, Naina; Lajoie, Stephane; Smole, Ursula et al. (2018) Dysregulated invertebrate tropomyosin-dectin-1 interaction confers susceptibility to allergic diseases. Sci Immunol 3:
Dyjack, Nathan; Goleva, Elena; Rios, Cydney et al. (2018) Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype. J Allergy Clin Immunol 141:1298-1309
Evans, Christopher M; Seibold, Max A; Gerber, Anthony N (2018) SPDEFending the Lung through Mucin Expression. Am J Respir Cell Mol Biol 59:287-288
Neophytou, Andreas M; Oh, Sam S; White, Marquitta J et al. (2018) Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma. Thorax 73:1041-1048
Zeiger, Andrew M; White, Marquitta J; Eng, Celeste et al. (2018) Genetic Determinants of Telomere Length in African American Youth. Sci Rep 8:13265
Mangul, Serghei; Yang, Harry Taegyun; Strauli, Nicolas et al. (2018) ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol 19:36
Sun, Xiaobo; Gao, Jingjing; Jin, Peng et al. (2018) Optimized distributed systems achieve significant performance improvement on sorted merging of massive VCF files. Gigascience 7:
Mak, Angel C Y; White, Marquitta J; Eckalbar, Walter L et al. (2018) Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. Am J Respir Crit Care Med 197:1552-1564
Park, Danny S; Eskin, Itamar; Kang, Eun Yong et al. (2018) An ancestry-based approach for detecting interactions. Genet Epidemiol 42:49-63