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: 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
• 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

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）：与欧洲裔美国人相比，非洲裔美国人更容易患哮喘，并且出现严重哮喘并发症的可能性几乎是欧洲裔美国人的三倍。全基因组关联研究已经确定了许多哮喘的遗传风险标记，但在欧洲和欧洲裔美国人患者中观察到的许多关联并未在非裔美国人个体中复制。这可能是等位基因频率、连锁不平衡或因祖先而异的疾病相关基因的结果。转录组的详细表征可以通过规避上述仅与基因型关联相关的一些问题来帮助鉴定哮喘相关基因。因此，该提案寻求结合转录组学和基因组学来鉴定哮喘相关基因以及似乎调节这些基因的表达数量性状基因座（eQTL）。我们建议使用 RNA 测序 (RNA-seq) 来表征患有和不患有哮喘的非裔美国人个体的转录组。 RNA-seq 在量化转录本丰度方面优于传统微阵列，但该方法迄今为止尚未在美国少数族群中广泛使用。按种族分类的哮喘表型和药物基因组相互作用研究 (SAPPHIRE) 队列是结合这些分析方法的理想组。 SAPPHIRE 不仅是美国规模最大、特征最好的哮喘队列之一，而且还拥有大量 SAPPHIRE 参与者的全基因组基因型数据和库存全血 RNA。在具体目标 1 中，我们将使用 RNA-seq 来根据哮喘状况来识别非裔美国人个体中先前确定的哮喘相关基因的表达差异。然后，预先存在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。由此产生的潜在新颖的、祖先特异性的哮喘基因也将进行 eQTL 评估。作为非裔美国人 SAPPHIRE 参与者的一个子集，他们在初始评估和哮喘恶化时收集了 RNA，在具体目标 3 中，我们将评估前述目标中确定的基因是否也与哮喘恶化相关。最后，具体目标 4 将尝试在另一组患有或不患有哮喘的非洲裔美国参与者中复制我们的研究结果。总之，哮喘是一种复杂的疾病，其祖先可能具有不同的遗传预测因子。不同种族的哮喘并发症持续存在不平等，这凸显了改进疾病生物标志物和治疗靶点的必要性。作为朝这个方向迈出的一步，我们提供了一种具有更强统计能力的综合方法来识别哮喘相关基因及其调控元件。