Asthma is one of the most common, chronic diseases. Its pathogenesis reflects complex interactions between genetic and environmental factors. We propose that the genes that influence asthma-associated quantitative traits have sex-specific effects and/or interact with environmental factors to determine risk for disease. In this application, we propose to study 9 QTs that are associated with asthma and bronchial hyperresponsiveness (BHR) in the Hutterites, a founder population of European origins that lives communally. Genome-screens have identified 12 genome-wide significant signals in 10 regions for 5 asthma- associated quantitative traits, nearly all of which have sex-specific effects. The overall objectives of our studies are to identify the genes that influence asthma-associated quantitative traits in the Hutterites, and to characterize their effects on the development and course of disease in well-characterized outbred populations and in functional studies. We propose three specific aims: 1) Conduct 10+ year follow-up studies in >1,000 Hutterites and collect additional phenotypes, including fractional exhaled nitric oxide (FeNO);2) Perform genome-wide association (GWA) studies to identify additional asthma associated quantitative trait loci (QTL) in the Hutterites using Affymetrix GeneChip?1/2 500k Array;and 3) Identify genes in regions linked to or associated with asthma-related quantitative traits, characterize their function and mechanism for sex- specific effects, and elucidate the relationship between genotype and disease risk and pathogenesis. The spectrum of asthma-associated QTs under investigation and the explicit recognition of the importance of sex- specific genetic effects will facilitate gene identification and ultimately provide novel insights into asthma pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085197-04
Application #
7808789
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Banks-Schlegel, Susan P
Project Start
2007-05-10
Project End
2011-12-31
Budget Start
2010-04-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$900,286
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Ober, Carole; Sperling, Anne I; von Mutius, Erika et al. (2017) Immune development and environment: lessons from Amish and Hutterite children. Curr Opin Immunol 48:51-60
Igartua, Catherine; Mozaffari, Sahar V; Nicolae, Dan L et al. (2017) Rare non-coding variants are associated with plasma lipid traits in a founder population. Sci Rep 7:16415
Igartua, Catherine; Davenport, Emily R; Gilad, Yoav et al. (2017) Host genetic variation in mucosal immunity pathways influences the upper airway microbiome. Microbiome 5:16
Papachristou, Charalampos; Ober, Carole; Abney, Mark (2016) A LASSO penalized regression approach for genome-wide association analyses using related individuals: application to the Genetic Analysis Workshop 19 simulated data. BMC Proc 10:221-226
Sengupta, Subhajit; Gulukota, Kamalakar; Zhu, Yitan et al. (2016) Ultra-fast local-haplotype variant calling using paired-end DNA-sequencing data reveals somatic mosaicism in tumor and normal blood samples. Nucleic Acids Res 44:e25
Ober, Carole (2016) Asthma Genetics in the Post-GWAS Era. Ann Am Thorac Soc 13 Suppl 1:S85-90
Cusanovich, Darren A; Caliskan, Minal; Billstrand, Christine et al. (2016) Integrated analyses of gene expression and genetic association studies in a founder population. Hum Mol Genet 25:2104-2112
Burrows, Courtney K; Kosova, Gülüm; Herman, Catherine et al. (2016) Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes. PLoS Genet 12:e1005858
Bønnelykke, Klaus; Ober, Carole (2016) Leveraging gene-environment interactions and endotypes for asthma gene discovery. J Allergy Clin Immunol 137:667-79
Çal??kan, Minal; Baker, Samuel W; Gilad, Yoav et al. (2015) Host genetic variation influences gene expression response to rhinovirus infection. PLoS Genet 11:e1005111

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