Mendelian Disease - Asthma Comorbidity to Find Subgroup-Specific Asthma Genes

孟德尔病 - 哮喘合并症寻找亚组特异性哮喘基因

• 批准号: 9130935
• 负责人: Carole Ober
• 金额: $ 77.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130935
• 关键词: Age; Amalgam; Asthma; Biological; Biological Process; Candidate Disease Gene; Cells; Characteristics; Clinical; Collection; Comorbidity; Complex; Computer Simulation; Computerized Medical Record; Data; Data Set; Databases; Deposition; Disease; Disease susceptibility; Environmental Exposure; Epithelial; Evaluation; Functional disorder; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genets; Genotype; Health; Hypersensitivity; Immune system; Individual; Inflammation; Inherited; Investments; Lead; Lung; Mendelian disorder; Molecular; Mutation; National Institute of Allergy and Infectious Disease; Nature; Obesity; Obstruction; Odds Ratio; Pathogenesis; Patients; Pattern; Phenotype; Population; Recording of previous events; Subgroup; Syndrome; Testing; Variant; airway inflammation; asthmatic patient; atopy; base; billing data; electronic data; gene function; gene product; genetic risk factor; genetic variant; insight; men; mucus hypersecretion; novel strategies; patient subsets; programs; protective effect; respiratory smooth muscle; response; stem

 DESCRIPTION (provided by applicant): Asthma is a heterogeneous, complex syndrome that undoubtedly represents an amalgam of multiple distinct "diseases", each stemming from a different constellation of gene variations and environmental exposure histories that results in a generally similar diathesis of episodic airflow obstruction, constrictor hyperresponsiveness, mucus hypersecretion, and airway wall inflammation and remodeling. Here, we propose to identify differential genetic contributions to asthma subgroups using a novel approach in which Mendelian diseases (MDs) are used as surrogate genetic markers. Asthma, much more common than MDs, occurs both in patients with or without any particular MD. However, if asthma is overrepresented among patients with a MD relative to those without that disease, then having that MD constitutes a genetic risk factor for asthma, and the association fur- ther implicates non-MD-causing variations in one of the MD-causing genes in the pathogenesis of asthma. Even though MDs are rare, examination of extremely large (administrative/billing or electronic medical record- derived) datasets that document both common and Mendelian diseases allows for such odds-ratio calculation. In Specific Aim #1, we will apply an in silico pipeline to data from >100 million individuals that identifies asthma subgroup specifically-associated MDs, then prioritizes their underlying genes for biological evaluation in Specific Aim #2. These studies will provide new insights into the distinguishing molecular mechanisms underlying pathogenetically distinct asthma subgroups. Moreover, successful completion of these studies will establish an entirely new paradigm for unraveling complex common diseases, based on their co-occurrence with Mendelian diseases as documented in extremely large databases.

 描述（由申请人提供）：哮喘是一种异质性的复杂综合征，其无疑代表多种不同“疾病”的混合物，每种疾病都源于不同的基因变异和环境暴露史，导致发作性气流阻塞、收缩肌高反应性、粘液高分泌和气道壁炎症和重塑的基本相似的素质。在这里，我们建议使用一种新的方法，其中孟德尔疾病（MD）被用作替代遗传标记，以确定不同的遗传贡献哮喘亚组。哮喘，比MD更常见，发生在有或没有任何特定MD的患者中。然而，如果哮喘在患有MD的患者中相对于那些没有这种疾病的患者来说是过度的，那么患有这种MD就构成了哮喘的遗传风险因素，并且这种关联进一步暗示了在哮喘的发病机制中的一种MD引起基因中的非MD引起的变异。尽管MD是罕见的，但对记录常见疾病和孟德尔疾病的极大（管理/计费或电子医疗记录衍生的）数据集的检查允许这样的比值比计算。在具体目标#1中，我们将对来自> 1亿个体的数据应用计算机模拟管道，以识别哮喘亚组特异性相关的MD，然后在具体目标#2中优先考虑其潜在基因进行生物学评价。这些研究将提供新的见解，区分分子机制的基础上不同的哮喘亚组的发病机制。此外，这些研究的成功完成将建立一个全新的范式，以解开复杂的常见疾病，根据他们的共同发生与孟德尔疾病记录在非常大的数据库。