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：
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
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/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

项目摘要

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.

非裔美国人患哮喘的可能性更高，几乎是非裔美国人的三倍与欧洲裔美国人相比，他们经历了严重的哮喘并发症。全基因组关联研究已经确定了许多哮喘的遗传风险标记，但许多关联在欧洲和欧洲裔美国人患者中观察到的情况并未在非洲裔美国人个体中复制。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，这些基因的差异在于祖先。转录组的详细表征有助于识别哮喘相关基因通过规避上述一些仅与基因型关联相关的问题。因此，该提案寻求结合转录组学和基因组学来识别哮喘相关基因并表达数量性状位点（eQTL）似乎调节这些基因。我们建议使用RNA 测序（RNA-seq）来表征非洲裔美国人个体的转录组特征哮喘。 RNA-seq 在量化转录本丰度方面优于传统微阵列，但这种方法迄今为止尚未在美国少数族裔中广泛使用。哮喘表型的研究和种族-民族的药物基因组相互作用 (SAPPHIRE) 队列是一个理想的群体，其中结合了这些分析方法。除了是美国规模最大、特征最鲜明的哮喘群体之一之外，大量 SAPPHIRE 已存在全基因组基因型数据和库存全血 RNA 参与者。在具体目标 1 中，我们将使用 RNA-seq 来识别先前识别的表达差异按哮喘状况划分的非洲裔美国人哮喘相关基因。预先存在的基因型数据将然后用于识别这些差异表达的哮喘相关基因的 eQTL。在具体目标 2 中，我们将使用混合图谱来识别祖先与哮喘相关的染色体区域。这些区域的基因将根据哮喘状态进行差异表达的检测。由此产生的潜在的新颖的、祖先特异性的哮喘基因也将被评估为 eQTL。作为非洲的一个子集美国 SAPPHIRE 参与者在初次评估和哮喘发作时收集了 RNA 恶化，在具体目标 3 中，我们将评估前面目标中确定的基因是否也是与哮喘恶化有关。最后，具体目标 4 将尝试在患有和不患有哮喘的非洲裔美国参与者分别为一组。总而言之，哮喘是一种复杂的疾病因祖先而具有潜在不同遗传预测因子的疾病。哮喘并发症中持续存在的不平等按种族强调需要改进疾病生物标志物和治疗靶点。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监管要素。