Asthma is the most common chronic disease of childhood, accounting for significant morbidity and reduced quality of life. Like many other chronic diseases, asthma is thought to result from a complex interplay between genes and environment. Although the advent of genome wide scans has provided us with rich datasets of polymorphisms in thousands of genes, utilization of this overwhelming amount of data for gene by environment interaction studies remains challenging. Genome wide expression (mRNA) signals generated in response to exposures of interest can help us focus genome wide data, so that only polymorphisms in relevant gene- activation pathways are tested in gene by environment interaction models. One important environmental factor, known to influence both asthma incidence and asthma severity, is exposure to bacteria and mold in the environment. Microbial components called PAMPs (pathogen associated molecular patterns) can modulate the immune system in ways that either decrease susceptibility to asthma or, alternatively, worsen airway inflammation and wheeze. This proposal outlines an integrative genomics strategy for studying how genetic polymorphisms alter the effects of microbial exposures on asthma phenotypes in five cohorts. First, we will analyze genome wide expression (mRNA) profiles of PAMP-stimulated immune cells to identify gene targets for interaction with environmental microbes. Next, we will determine if polymorphisms in these genes, either individually or as SNP sets in functionally related genes, modify the effects of environmental bacteria and fungi on asthma incidence and severity. Finally, we will examine how epigenetic modifications (DNA methylation) of PAMP signaling genes alter gene expression in response to microbial stimuli.

Public Health Relevance

The K99/R00 grant proposes to identify novel gene by environment interactions in asthma incidence and asthma severity by integrating genome wide expression profiles, genetic polymorphisms and epigenetic data. This research will uncover genetic polymorphisms and epigenetic modifications that modify an individual's risk of asthma development or asthma exacerbation in response to bacteria and mold in the environment. These genetic susceptibility markers will help us to better understand asthma pathogenesis, and will also allow us to focus environmental interventions on those individuals who would benefit most.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL109162-02
Application #
8301583
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (M1))
Program Officer
Tigno, Xenia
Project Start
2011-07-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$137,160
Indirect Cost
$10,160
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sharma, Sunita; Poon, Audrey; Himes, Blanca E et al. (2012) Association of variants in innate immune genes with asthma and eczema. Pediatr Allergy Immunol 23:315-23
Sordillo, Joanne E; Sharma, Sunita; Poon, Audrey et al. (2011) Effects of endotoxin exposure on childhood asthma risk are modified by a genetic polymorphism in ACAA1. BMC Med Genet 12:158