Asthma affects over 17 million people in the United States, and is a significant cause of morbidity. Development of novel therapies to reduce asthma burden is a major priority of the scientific community, yet such studies are often hampered by the limited availability of clinically relevant biologic samples for investigation. The primary objective of this proposal is to establish the Asthma BioRepository for Integrative Genomic Research, an open-access collection of immortalized cell lines, cDNA and DNA, and an accompanying complementary dataset for these samples consisting of extensive phenotype data, and genome-wide SNP genotype, gene expression, and methylation data from more than 2,700 well-characterized subjects participating in ongoing genetic and genomic studies of asthma. This Asthma BioRepository will be established through the EVE Consortium, a collaborative effort consisting of U.S. investigators from 11 academic centers who have conducted genome-wide association studies (GWAS) of asthma. The EVE cohorts together total more than 30,000 subjects with genome-wide SNP data and provide broad representation of the North American asthmatic population. The Asthma BioRepository will be developed through the following three Specific Aims.
In Specific Aim 1, blood samples and asthma-relevant primary cell types (including CD4+ peripheral blood lymphocytes, peripheral blood mononuclear cells, alveolar macrophages, and lung biopsy specimens) will be collected for gene expression profiling and DNA methylation studies. Lymphoblastic cell lines will also established.
Specific Aim 2 focuses on the development of an accompanying database consisting of genome-wide gene expression and DNA methylation profiles for all of the collected samples and 25% of the immortalized cell lines to facilitate comprehensive integrative genomic analysis. This database will be linked to clinical and genome-wide genotype data (in dbGAP), and together with the collected biological specimens and cell lines, the totality of the Asthma BioRepository will be submitted to the NHLBI Biologic Specimen Repository and Data Repository Information Coordinating Center (BioLINCC) for distribution to the scientific community.
Specific Aim 3 will use the developed database to perform comprehensive integrative genomic analyses to identify the regulatory genetic variation critical to asthma pathogenesis. These studies will include expression profiling of asthma severity;genome-wide expression quantitative trait (eQTL) mapping;comparison of gene expression profiles and identified eQTLs across asthma-relevant tissues;and genomewide association studies of methylation patterns in asthma. Results of these studies will be submitted to dbGAP and linked to the Asthma BioRepository database to provide investigators with preliminary candidate loci for future investigation. The Asthma BioRepository for Integrative Genomic Research will represent the largest collection of asthma-related biological materials and genomic data in the world, and an invaluable resource for asthma researchers everywhere.
The Asthma BioRepository for Integrative Genomic Research would represent the largest collection of asthma cell lines and accompanying biologic data in the world and would facilitate comprehensive, large-scale molecular analysis in some of the best-characterized asthma populations in existence. A centralized biorepository of asthma-related biological samples and viable cell lines from more than 2,700 representative asthmatics would provide the scientific community with an unprecedented source of materials to support ongoing and future investigations and functional studies of the molecular determinants of asthma susceptibility, its natural history, and pharmacogenetics. This repository would represent an everlasting source of diverse clinical samples available for researchers with more limited access to clinical samples, thus removing a common obstacle in bench research.
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