Effects of Rare Variants and Ancestry on Beta Agonist Response in Asthma and COPD

罕见变异和血统对哮喘和慢性阻塞性肺病 (COPD) β 受体激动剂反应的影响

• 批准号: 10533637
• 负责人: Victor E. Ortega
• 金额: $ 73.8万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-02 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533637
• 关键词: ADRB2 gene; Admixture; Adrenal Cortex Hormones; Adrenergic Receptor; Adverse effects; Affect; African; African American; African American population; African ancestry; Agonist; Airway Disease; Albuterol; Area; Asthma; Biological; Cessation of life; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; DNA Resequencing; Data; Data Set; Disease; Ethnic group; G Protein-Coupled Receptor Signaling; Genes; Genetic; Genetic Variation; Genetic study; Genotype; Hispanic; Individual; Inflammatory; Inhalation; Life; Measures; Not Hispanic or Latino; Pathway Analysis; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacogenetics; Play; Receptor Gene; Reporting; Research; Risk; Role; Safety; Severity of illness; Signal Pathway; Subgroup; Therapeutic; Treatment Failure; Variant; Weight; admixture mapping; adverse outcome; asthma exacerbation; base; beta-2 Adrenergic Receptors; caucasian American; cohort; ethnic difference; exome sequencing; gene interaction; genetic approach; genetic predictors; genetic variant; genome analysis; genome sequencing; genome wide association study; insertion/deletion mutation; molecular phenotype; multi-ethnic; next generation sequencing; novel; power analysis; programs; prospective; pulmonary function; randomized trial; rare variant; response; safety study; treatment response; whole genome

SUMMARY Surveillance trials suggest that the risk for life-threatening asthma exacerbations and asthma-related deaths are increased with long-acting β2-adrenergic receptor (β2AR) agonist (LABA) therapy, although prospective randomized trials, including FDA-mandated safety studies, have not confirmed these observations when LABA is combined with an inhaled corticosteroid (ICS). Despite this, the risk for adverse outcomes and treatment failure during LABA therapy is higher in African Americans compared to Whites. We have shown that rare genetic variants in the β2-adrenergic receptor gene (ADRB2) are associated with exacerbations in asthma subjects taking LABAs. We have also shown that African ancestry is strongly associated with lower lung function in African Americans with severe asthma and COPD. These data provide a strong rationale for using conventional and functional genetic approaches to elucidate role of ancestry-specific genetic variation, including novel variants and variation in important components of the β2AR signaling pathway, that determine beta agonist response and lung function. We hypothesize that ethnic-specific genetic variants, particularly rare variants and β2AR pathway variation, have important effects on beta agonist response and baseline lung function. We propose the following Specific Aims: Aim 1: To identify novel genetic variants associated with beta agonist response and measures of lung function in multi-ethnic asthma and COPD cohorts using a combination of rare variant-based, admixture-based whole-genome analyses, and GWAS. We will leverage existing comprehensive genotyping with imputation and Next- Generation Sequencing (NGS) datasets from 1,919 asthma subjects from SARP1-3, 839 subjects from Asthma Clinical Research Network trials, 2,807 (1,122 African/African American and 554 Hispanic) asthma subjects from three LABA-ICS clinical trials, and 2,507 SPIROMICS subjects for the discovery of novel gene pathways associated with beta agonist response and lung function. Aim 2: To validate the effects of variants in the β2-adrenergic receptor (β2AR) pathway and novel gene pathways on beta agonist response and lung function in multi-ethnic beta agonist-treated clinical trial cohorts. We will perform de novo NGS on 40 β2AR pathway genes and utilize existing whole-genome sequencing data for β2AR pathway analyses to identify novel gene-gene interactions constituting predictive genetic profiles for beta agonist response and lung function across ethnic groups .Aim 3: To validate the biologic effects of rare variants within the β2AR signaling pathway in order to refine and support genetic predictive profiles of beta agonist therapeutic responsiveness. β2AR pathway rare variation will be evaluated with molecular phenotyping to refine predictive genetic profiles. The proposed studies have the potential to define an at-risk subgroup of asthma susceptible to adverse effects of LABA therapy while identifying novel loci for beta agonist response or disease severity and elucidating novel mechanisms for inter-ethnic differences.

概括 监测试验表明，危及生命的哮喘恶化和哮喘相关死亡的风险 长效 β2 肾上腺素能受体 (β2AR) 激动剂 (LABA) 治疗会增加，尽管前瞻性 随机试验，包括 FDA 授权的安全性研究，尚未证实 LABA 时的这些观察结果 尽管如此，仍存在不良结果和治疗的风险。 与白人相比，LABA 治疗失败的比例在非裔美国人中更高。我们已经证明这种情况很少见。 β2-肾上腺素能受体基因 (ADRB2) 的遗传变异与哮喘恶化有关 我们还表明，非洲血统与下肺密切相关。 这些数据为患有严重哮喘和慢性阻塞性肺病的非裔美国人提供了强有力的理由。 阐明祖先特异性遗传变异作用的常规和功能遗传方法， 包括β2AR信号通路重要组成部分的新变体和变异，这决定了 我们与种族特异性遗传变异作斗争，尤其是β激动剂反应和肺功能。 罕见变异和β2AR途径变异，对β激动剂反应有重要影响 我们提出以下具体目标： 目标 1：识别新的基因。 与多种族哮喘中β受体激动剂反应相关的变异和肺功能测量 和慢性阻塞性肺病队列使用基于罕见变异、基于混合的全基因组的组合 我们将利用现有的综合基因分型与插补和下一步。 来自 SARP1-3 的 1,919 名哮喘受试者、来自哮喘的 839 名受试者的世代测序 (NGS) 数据集 临床研究网络试验，2,807 名（1,122 名非洲裔/非裔美国人和 554 名西班牙裔）哮喘受试者 来自三项 LABA-ICS 临床试验和 2,507 名 SPIROMICS 受试者，用于发现新的基因途径 与 β 激动剂反应和肺功能相关 目标 2：验证变异的影响。 β2-肾上腺素能受体（β2AR）途径和β激动剂反应和肺的新基因途径 我们将对 40 名 β 受体激动剂治疗的临床试验队列进行从头 NGS 的研究。 β2AR 通路基因并利用现有的全基因组测序数据进行 β2AR 通路分析 识别新的基因-基因相互作用，构成β激动剂反应和肺的预测遗传图谱 跨种族群体的功能。目标 3：验证 β2AR 内罕见变异的生物学效应 信号通路，以完善和支持 β 激动剂治疗的遗传预测谱 β2AR途径罕见变异将通过分子表型分析进行评估以进行改进。 所提出的研究有可能定义一个高危亚组。 哮喘易受 LABA 治疗的副作用影响，同时确定 β 激动剂的新位点 反应或疾病严重程度并阐明种族间差异的新机制。