This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Asthma affects over 14 million people in the United States.1 The prevalence of asthma in the U.S. increased by 74.9% from 1980 to 1996; 1 ethnic minority populations such as Puerto Ricans are disproportionately represented in this trend of increasing asthma morbidity. 2, 3 Puerto Ricans had the highest age-adjusted asthma mortality from 1990 to 1995 among U.S. Hispanics in general and among Hispanics in the U.S. Northeast in particular. Although asthma is a major public health problem among Puerto Ricans, little is known about the contribution of genetic and environmental factors to asthma in this population. 5 To date, results of genome-wide analyses for linkage to asthma phenotypes have been published by 11 groups in 13 distinct populations. 6-17 None of these genome scans included Puerto Ricans. Because of the high prevalence of single-parent households among Puerto Ricans in the U.S. mainland,18 family-based studies of genetic association would be difficult to perform in this population. A population-based case-control study of genetic association for asthma and asthma-related phenotypes among Puerto Ricans in the U.S mainland is feasible and would offer a unique opportunity to examine genetic and environmental risk factors in a minority population with high asthma morbidity. We have recruited children with asthma in Hartford (Connecticut) as part of a program to improve asthma management by physicians in this community.19 In these children, we have shown that Puerto Rican ethnicity is associated with sensitization to specific allergens and increased asthma severity.20, 21 Among school children in Hartford, we have collected data in a group of Puerto Rican children with asthma (cases) and a group of Puerto Rican children without asthma (controls). We propose to conduct a case-control study of association between selected genetic and environmental factors and asthma in Puerto Ricans. Between 75% and 94% of Puerto Rican children with asthma are atopic (see C.4.c).22 In atopic children, production of cytokines (IL-4, IL-5, IL-9, and IL-13) by T-helper (Th)2 cells promotes increased production of immunoglobulin E (IgE), eosinophilia, mast cell differentiation, and long-term expression of allergen-specific immunity.23,24 Atopy and atopic asthma may result from lack of upregulation of Th1 immune responses and/or inadequate downregulation of Th2 immune responses.25, 26 We hypothesize that single nucleotide polymorphisms (SNPs) in genes that control the development and regulation of Th1 cells, Th2 cells, and regulatory T cells (Tregs) are associated with asthma and/or intermediate phenotypes of asthma (asthma phenotypes') in Puerto Rican children. We further hypothesize that parental report of exposure to pets in early life (during pregnancy and/or the first year of life) is associated with reduced risks of asthma and atopy, and that current exposure to high levels of indoor allergens is associated with a) increased asthma severity and abnormal lung function phenotypes (reduced FEV1 and FEV1/FVC, increased airway responsiveness, and reduced bronchodilator responsiveness) in Puerto Rican children with asthma and b) atopy phenotypes (e.g., increased serum total IgE) in Puerto Rican children with and without asthma. In addition, we hypothesize that variants in genes that control the development and regulation of Th1 cells, Th2 cells, and Tregs interact with indoor allergen exposures in influencing asthma and asthma severity in Puerto Rican children. To test these hypotheses, we will pursue the following specific aims: 1. To recruit 500 Puerto Rican children with asthma (cases) and 500 Puerto Rican children without asthma (control subjects). 2. To test for association between Single Nucleotide Polymorphisms (SNPs) in 20 positional candidate genes and i) asthma (in all subjects), ii) lung function phenotypes (airway responsiveness, FEV1, FEV1/FVC, and bronchodilator response)and atopy phenotypes (skin test reactivity to allergens, serum total and allergen-specific IgE, and eosinophil count) separately in cases and in control subjects, and iii) asthma severity in cases. 3a. To examine whether i) parental report of exposure to pets (dogs and/or cats) in early life is associated with reduced risks of asthma (in all subjects) and atopy (separately in cases and in control subjects), and b) current exposure to indoor allergens (dust mite, cockroach, dog, cat, mouse, and rat) is associated with increased asthma severity and abnormal lung function phenotypes in cases, and with atopy phenotypes separately in cases and in control subjects. 3b. To examine interactions between exposure to the indoor allergens outlined in Specific Aim 3a and SNPs in the candidate genes selected in Specific Aim 2.
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