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

摘要 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 使用长效β2肾上腺素能受体(β2AR)激动剂(LABA)治疗会增加，尽管 随机试验，包括FDA规定的安全性研究，尚未证实这些观察结果，当LABA 与吸入性皮质类固醇(ICS)联合使用。尽管如此，不良后果和治疗的风险 与白人相比，非裔美国人在LABA治疗中的失败率更高。我们已经证明了稀有的 β2-肾上腺素能受体基因的遗传变异与哮喘的恶化有关 参加LABA课程的受试者。我们还表明，非洲血统与下肺密切相关。 患有严重哮喘和慢性阻塞性肺病的非裔美国人的功能。这些数据为使用这些数据提供了强有力的理由 传统的和功能的遗传学方法来阐明祖先特有的遗传变异的作用， 包括β2AR信号通路重要组成部分的新变体和变异，它们决定了 β受体激动剂反应和肺功能。我们假设特定种族的基因变异，特别是 罕见的突变体和β2AR途径的变异，对β激动剂的反应和 基线肺功能。我们提出了以下具体目标：目标1：识别新的基因 多民族哮喘患者中与β-激动剂反应和肺功能测量相关的变异 和COPD队列使用罕见的基于变异的、基于混合的全基因组的组合 分析，和GWAs。我们将利用现有的全面基因分型和归罪，下一步- 来自SARP1-3的1,919名哮喘患者的代序列(NGS)数据集，839名哮喘患者 临床研究网络试验，2,807名(1,122名非洲人/非裔美国人和554名西班牙裔)哮喘患者 来自三个LABA-ICS临床试验和2,507个SPROMICS受试者发现新的基因途径 与β受体激动剂反应和肺功能有关。目标2：验证变种在基因中的作用 β-2-肾上腺素能受体(β-2AR)途径和新基因途径在β-激动剂反应和肺组织中的作用 多种族β受体激动剂治疗的临床试验队列中的作用。我们将在40个月进行新的NGS β2AR途径基因，并利用现有的全基因组测序数据进行β2AR途径分析 确定构成β-激动剂反应和肺的预测遗传图谱的新的基因-基因相互作用 跨种族的功能。目标3：验证β2AR内罕见变异的生物效应 信号通路以提炼和支持β-激动剂治疗的基因预测谱 响应性。β2AR途径罕见变异将用分子表型进行评估以提炼 预测性基因图谱。拟议的研究有可能定义一个风险亚组 哮喘易受LABA治疗不良反应的影响，同时寻找β-激动剂的新基因 反应或疾病严重程度，并阐明种族间差异的新机制。

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.