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.
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.
|Sharma, Amitabh; Kitsak, Maksim; Cho, Michael H et al. (2018) Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module. Sci Rep 8:14439|
|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|
|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|
|Forno, Erick; Sordillo, Joanne; Brehm, John et al. (2017) Genome-wide interaction study of dust mite allergen on lung function in children with asthma. J Allergy Clin Immunol 140:996-1003.e7|
|Kelly, Rachel S; Virkud, Yamini; Giorgio, Rachel et al. (2017) Metabolomic profiling of lung function in Costa-Rican children with asthma. Biochim Biophys Acta Mol Basis Dis 1863:1590-1595|
|Weiss, Scott T (2017) Emerging mechanisms and novel targets in allergic inflammation and asthma. Genome Med 9:107|
|Forno, Erick; Weiner, Daniel J; Mullen, James et al. (2017) Obesity and Airway Dysanapsis in Children with and without Asthma. Am J Respir Crit Care Med 195:314-323|
|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|
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