The Asthma BioRepository for Integrative Genomics Research

描述（由申请人提供）： 在美国，哮喘影响超过1700万人，并且是发病的重要原因。 开发新的治疗方法以减轻哮喘负担是科学界的一个主要优先事项，但此类研究往往受到临床相关生物样本有限的阻碍。该提案的主要目标是建立用于整合基因组研究的哮喘生物储存库，这是一个永生化细胞系，cDNA和DNA的开放获取集合，以及这些样本的附带补充数据集，包括广泛的表型数据，以及来自超过2，700名参与正在进行的哮喘遗传和基因组研究的特征明确的受试者。这个哮喘生物库将通过EVE联盟建立，该联盟由来自11个学术中心的美国研究人员组成，他们进行了哮喘的全基因组关联研究（GWAS）。EVE队列总共有超过30，000名具有全基因组SNP数据的受试者，并提供了北美哮喘人群的广泛代表性。哮喘生物库将通过以下三个具体目标进行开发。在特定目标1中，将采集血液样本和哮喘相关原代细胞类型（包括CD 4+外周血淋巴细胞、外周血单核细胞、肺泡巨噬细胞和肺活检标本）用于基因表达谱分析和DNA甲基化研究。还将建立淋巴母细胞系。具体目标2的重点是开发一个附带的数据库，包括所有收集的样本的全基因组基因表达和DNA甲基化谱， 25%的永生化细胞系，以促进全面的整合基因组分析。该数据库将与临床和全基因组基因型数据（在dbGAP中）链接，并与收集的生物标本和细胞系一起，将哮喘BioRepository的整体提交给NHLBI生物标本库和数据库信息协调中心（BioLINCC），以分发给科学界。具体目标3将使用已开发的数据库进行全面的综合基因组分析，以确定对哮喘发病机制至关重要的调节遗传变异。这些研究将包括哮喘严重程度的表达谱;全基因组表达数量性状（eQTL）定位;比较基因表达谱和哮喘相关组织中鉴定的eQTL;以及哮喘甲基化模式的全基因组关联研究。这些研究的结果将提交给dbGAP，并链接到哮喘BioRepository数据库，为研究者提供初步的候选基因座，供未来研究使用。整合基因组研究的哮喘生物库将代表世界上最大的哮喘相关生物材料和基因组数据的集合，也是世界各地哮喘研究人员的宝贵资源。 (End摘要）

DESCRIPTION (provided by applicant): 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. (End of Abstract)