The marked diversity of U.S. Hispanics is a major barrier for identification of asthma-susceptibility genes in this ethnic group. This proposal seeks to identify asthma-susceptibility genes in a genetically isolated Hispanic population with high prevalence of asthma in the Central Valley of Costa Rica. With support from R01 HL66289, we have collected phenotypic and genotypic data in 2,504 individuals in the Central Valley (671 members of 8 large pedigrees of children with asthma, and 611 children with asthma and their parents [1,833 individuals]) since 2001. Among members of large families of children with asthma, we conducted genome-wide linkage analyses of asthma and its intermediate phenotypes, including airway responsiveness and total serum IgE. We identified two loci meeting genome-wide criteria for significant linkage to two critical intermediate phenotypes of asthma in Costa Ricans: airway responsiveness (in all subjects) and total serum IgE (in males). We are currently conducting the initial phase of fine-mapping association studies of asthma and airway responsiveness on chromosome 12q24 in 600 parent-child trios previously recruited for the parent grant for this proposal. On the basis of our findings to date, we hypothesize that a gene(s) on chromosome 12q24 influences asthma and airway responsiveness in Costa Ricans, and that a gene(s) on chr. 20p12 influences total serum IgE in male Costa Ricans. To test this hypothesis, we will genotype and test for association between linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) in chromosome 20p12 and total serum IgE in 900 individuals (300 boys with asthma and their parents) recruited for the parent grant. We will recruit 600 children with asthma and their parents (1,800 individuals). We will then genotype and test for association between SNPs in chromosomes 12q24 and 20p12 and asthma and/or its intermediate phenotypes (airway responsiveness and total serum IgE) in this new cohort for replication of our initial fine-mapping association studies, and identification of candidate genes for asthma and/or its intermediate phenotypes. We will then sequence 15 candidate genes in 24 Costa Rican children with asthma. Finally, we will genotype and test for association between SNPs and haplotypes in these genes and asthma and/or its intermediate phenotypes in 3,600 individuals (1,200 children with asthma and their parents) recruited for the parent grant and for the current application. ? ? ?
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