Combined Transcriptomics and Genomics to Find Asthma Genes in Admixed Populations

结合转录组学和基因组学在混合人群中寻找哮喘基因

• 批准号: 8629342
• 负责人: Keoki Williams
• 金额: $ 74.14万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629342
• 关键词: Accident and Emergency department; Admixture; Affect; African American; American; Asthma; Biological Markers; Blood specimen; Cessation of life; Child; Childhood Asthma; Chromosomes, Human, Pair 17; Clinical; Clinical Data; Clinical assessments; Complex; DNA; Data; Databases; Detection; Diagnosis; Disease; Enrollment; Environmental Exposure; Ethnic Origin; European; Evaluation; Gene Expression; Gene Expression Profile; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Techniques; Genetic Transcription; Genetic Variation; Genomics; Genotype; Health Services Accessibility; Health system; Hospitalization; Individual; Linkage Disequilibrium; MADD gene; Maps; Measures; Methods; Minority; Participant; Pathogenesis; Pathway interactions; Patient Self-Report; Patients; Pharmacogenomics; Phenotype; Population; Population Group; Population Study; Prevalence; Proteins; Pulmonary function tests; Quantitative Trait Loci; RNA; RNA Sequences; RNA Splicing; Race; Regulatory Element; Risk Marker; Single Nucleotide Polymorphism; TSLP gene; Time; Tissue-Specific Gene Expression; Transcript; United States; Variant; Visit; Whole Blood; base; cohort; disability; experience; genetic risk factor; genome wide association study; genome-wide; improved; new therapeutic target; next generation sequencing; novel; patient population; population based; public health relevance; therapeutic target; transcriptome sequencing; transcriptomics

African American individuals are more likely to develop asthma and are nearly three times as likely to experience serious asthma complications when compared with European American individuals. Genome wide association studies have identified a number of genetic risk markers for asthma, but many of the associations observed in European and European American patients have not replicated in African American individuals. This may be the result of allele frequencies, linkage disequilibria, or disease-related genes which differ by ancestry. Detailed characterization of the transcriptome can aid in the identification of asthma-related genes by circumventing some of the aforementioned problems associated with genotype association alone. Therefore, this proposal seeks to combine transcriptomics and genomics to identify asthma-related genes and the expression quantitative trait loci (eQTL) which appear to regulate these genes. We propose using RNA sequencing (RNA-seq) to characterize the transcriptome of African American individuals with and without asthma. RNA-seq is superior to traditional microarrays at quantifying transcript abundance, but this method has not been widely used in U.S. minority populations to date. The Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) cohort is an ideal group in which combine these analytic approaches. In addition to being one of largest and best characterized asthma cohorts in the U.S., genome wide genotype data and banked whole blood RNA already exist for a large number of SAPPHIRE participants. In Specific Aim 1, we will use RNA-seq to identify expression differences in previously identified asthma-related genes among African American individuals by asthma status. Pre-existing genotype data will then be used to identify eQTL for these differentially expressed, asthma-associated genes. In Specific Aim 2, we will use admixture mapping to identify chromosomal regions where ancestry is associated with asthma. The genes in these regions will be interrogated for differential expression by asthma status. The resulting potentially novel, ancestry-specific asthma genes will also be assessed for eQTL. As a subset of African American SAPPHIRE participants have RNA collected at both their initial evaluation and the time of an asthma exacerbation, in Specific Aim 3 we will assess whether the genes identified in the preceding aims are also associated with asthma exacerbations. Lastly, Specific Aim 4 will attempt to replicate our findings in a separate group of African American participants with and without asthma. In summary, asthma is a complex disease with potentially distinct genetic predictors by ancestry. Persisting inequities in asthma complications by race-ethnicity underscore the need for improved disease biomarkers and therapeutic targets. As a step in this direction, we proffer an integrative approach with greater statistical power to identify asthma-related genes and their regulatory elements.

非裔美国人更容易患哮喘， 与欧洲美国人相比，患有严重的哮喘并发症。全基因组 相关研究已经确定了一些哮喘的遗传风险标志物，但许多相关性 在欧洲和欧洲美国患者中观察到的结果在非洲裔美国人个体中没有复制。 这可能是等位基因频率、连锁不平衡或疾病相关基因的结果， 祖先转录组的详细特征可以帮助识别哮喘相关基因 通过规避与基因型关联单独相关的一些上述问题。 因此，这项提议试图将联合收割机转录组学和基因组学相结合，以确定哮喘相关基因， 表达数量性状基因座（eQTL）似乎调控这些基因。我们建议使用RNA 测序（RNA-seq）来表征具有和不具有 哮喘RNA-seq在定量转录本丰度方面上级传统的微阵列，但这种方法 至今尚未在美国少数民族中广泛使用。哮喘的表型及临床研究进展 人种-种族药物基因组学相互作用（SAPPHIRE）队列是一个理想的组，其中联合收割机结合了这些 分析方法。除了是美国最大和最具特征的哮喘队列之一， 对于大量的SAPPHIRE，已经存在全基因组基因型数据和库存的全血RNA 参与者在具体目标1中，我们将使用RNA-seq来鉴定先前鉴定的表达差异。 哮喘相关基因在非裔美国人个体哮喘状态。现有的基因型数据将 然后用于鉴定这些差异表达的哮喘相关基因的eQTL。在具体目标2中， 我们将使用混合作图法来鉴定祖先与哮喘相关的染色体区域。 这些区域中的基因将被哮喘状态询问差异表达。所得 潜在的新的、祖先特异性哮喘基因也将被评估eQTL。作为非洲人的子集 美国SAPPHIRE参与者在最初评估和哮喘发作时都收集了RNA 在具体目标3中，我们将评估在前面的目标中确定的基因是否也 与哮喘恶化有关。最后，具体目标4将试图复制我们的研究结果， 一组有哮喘和无哮喘的非裔美国人参与者。总之，哮喘是一种复杂的 疾病与潜在不同的遗传预测的祖先。哮喘并发症的持续不平等 强调了对改进的疾病生物标志物和治疗靶点的需要。作为一个步骤， 在这个方向上，我们提供了一种具有更大统计能力的综合方法来识别哮喘相关基因 及其调控因素。