4 R37 HL066289-10 - MERIT Extension Principal Investigator/Program Director (Last, First, Middle): WEISS, Scott T. PROJECT SUIVIMARY (See instructions): Asthma remains a major public health problem in the United States and worldwide affecting 300 million people in the US with health care costs of >20 billion dollars/year. Asthma Is a complex disease, likely influenced by genetic and environmental factors. Asthma genetic epidemiology has made significant progress identifying over 43 genes via candidate gene studies, 6 genes via linkage and fine mapping and 3 genes via genome-wide association studies (GWAS). Although asthma is a significant cause of morbidity among certain Hispanic groups in the US (e.g., Puerto Ricans) and Hispanic America (e.g., Costa Ricans), relatively few genetic studies have included Hispanic individuals. Most - but not all - Hispanics have variable proportions of European, Amerindian, and African ancestry, and there is marked variation in asthma prevalence and severity within Hispanic sub-populations, making genetic studies of asthma in Hispanics particularly challenging. To reduce this heterogeneity, we have been studying the genetics of asthma in a relatively homogeneous Hispanic population with high prevalence of asthma (~24% in adolescents) in the Central Valley of Costa Rica for the past 8 years. For this renewal, we have combined our Costa Rican population with the CAMP trios to attempt to identify all the genes for childhood asthma. We will continue to contribute to advancing our understanding of asthma genetics by using novel methods to find replicated asthma genes. In addition, multiple sets of studies are available for this grant application to provide the unique opportunity to identify genetic determinants of asthma that are specific to Hispanic populations, while, at the same time, universal genetic determinants that are relevant for Hispanic populations and Caucasian populations will be discovered. To identify these variants we will perform three different joint-analysis of the available GWAS: a joint analysis of Costa Rica and CAMP will be performed, followed by an in silico meta analysis of Costa Rica and Mexican trios from the EVE consortium and, finally, an overall analysis of Costa Rica, CAMP, and EVE. We believe that by conducting our proposed genome-wide association study, we will have the most powerful and comprehensive approach to identification of asthma-susceptibility genes, and our bioinformatics tools will allow us to take full advantage of information deriving from our experiments to create a bioinformatically-integrated program in ainway disease genetics.

Public Health Relevance

To date, there has been only one genome-wide association study of asthma and/or its intermediate phenotypes in a Hispanic (Mexican) population. Our study addresses an insufficiently studied problem: the genetics of asthma in Hispanic subgroups disproportionately affected by asthma: Hispanics in general and Costa Ricans in particular. This proposal should lead to the identification of asthma-susceptibility genes in general, and among Hispanics in particular.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37HL066289-13S1
Application #
8928781
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Gan, Weiniu
Project Start
2001-07-10
Project End
2016-03-31
Budget Start
2014-09-30
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
McGeachie, Michael J (2017) Childhood asthma is a risk factor for the development of chronic obstructive pulmonary disease. Curr Opin Allergy Clin Immunol 17:104-109
Kelly, Rachel S; Virkud, Yamini; Giorgio, Rachel et al. (2017) Metabolomic profiling of lung function in Costa-Rican children with asthma. Biochim Biophys Acta 1863:1590-1595
McGeachie, Michael J; Davis, Joshua S; Kho, Alvin T et al. (2017) Asthma remission: Predicting future airways responsiveness using an miRNA network. J Allergy Clin Immunol 140:598-600.e8
Weiss, Scott T (2017) Emerging mechanisms and novel targets in allergic inflammation and asthma. Genome Med 9:107
Brehm, John M; Man Tse, Sze; Croteau-Chonka, Damien C et al. (2015) A Genome-Wide Association Study of Post-bronchodilator Lung Function in Children with Asthma. Am J Respir Crit Care Med 192:634-7
Pino-Yanes, Maria; Gignoux, Christopher R; Galanter, Joshua M et al. (2015) Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos. J Allergy Clin Immunol 135:1502-10
Brehm, John M; Ramratnam, Sima K; Tse, Sze Man et al. (2015) Stress and Bronchodilator Response in Children with Asthma. Am J Respir Crit Care Med 192:47-56
Fleisch, Abby F; Rifas-Shiman, Sheryl L; Koutrakis, Petros et al. (2015) Prenatal exposure to traffic pollution: associations with reduced fetal growth and rapid infant weight gain. Epidemiology 26:43-50
Sordillo, Joanne E; Scirica, Christina V; Rifas-Shiman, Sheryl L et al. (2015) Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children. J Allergy Clin Immunol 135:441-8
Sordillo, Joanne E; Kelly, Roxanne; Bunyavanich, Supinda et al. (2015) Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity. J Allergy Clin Immunol 136:885-92.e2

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