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

基本信息

批准号：
8795754
负责人：
Keoki Williams
金额：
$ 71.83万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
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/8795754
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 Genomic Segment Genomics Genotype Health 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 differential expression disability experience genetic predictors genetic risk factor genome wide association study genome-wide improved new therapeutic target next generation sequencing novel patient population population based therapeutic target transcriptome sequencing transcriptomics

项目摘要

DESCRIPTION (provided by applicant): 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 inequitie 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.

描述（由申请人提供）：与欧美人相比，非裔美国人更有可能患哮喘，几乎可能经历严重的哮喘并发症。基因组广泛的关联研究已经确定了哮喘的许多遗传风险标志物，但是在欧美患者中观察到的许多关联尚未在非裔美国人中复制。这可能是由于等位基因频率，连锁不平衡或疾病相关的基因而与祖先不同的结果。转录组的详细表征可以通过规避与基因型关联相关的一些上述问题来帮助鉴定与哮喘相关的基因。因此，该建议试图结合转录组学和基因组学以鉴定哮喘相关基因和表达定量性状基因座（EQTL），这些基因座（EQTL）似乎调节了这些基因。我们建议使用RNA测序（RNA-SEQ）来表征患有和没有哮喘的非洲裔美国人的转录组。 RNA-Seq在量化转录本丰度时优于传统的微阵列，但是迄今为止，这种方法尚未被广泛用于美国少数群体。对种族种族（蓝宝石）队列的哮喘表型和药物基因组相互作用的研究是结合这些分析方法的理想群体。除了是美国最大，最佳特征的哮喘同龄人之一外，基因组广泛的基因型数据和储存的全血RNA已经存在于大量的蓝宝石参与者中。在特定目标1中，我们将使用RNA-Seq通过哮喘状况来识别非裔美国人个体中与哮喘相关基因的表达差异。然后，现有的基因型数据将用于识别这些差异表达的哮喘相关基因的EQTL。在特定的目标2中，我们将使用混合图映射来识别与哮喘相关的染色体区域。这些区域中的基因将通过哮喘状态质疑差异表达。还将评估由此产生的潜在新型祖先特异性哮喘基因的EQTL。作为非裔美国蓝宝石参与者的一部分，在其初始评估和哮喘患者的时间均收集了RNA，在特定的目标3中，我们将评估上述目标中鉴定的基因是否也与哮喘恶化有关。最后，特定的目标4将尝试在有和没有哮喘的一群非裔美国人参与者中复制我们的发现。总而言之，哮喘是一种复杂的疾病，具有祖先的潜在遗传预测因子。通过种族种族持续不平等哮喘并发症，强调了改善疾病生物标志物和治疗靶标的需求。作为朝这个方向发展的一步，我们提供了一种具有更大统计能力的综合方法，以识别与哮喘相关的基因及其调节元素。