Effects of Rare Variants and Ancestry on Beta Agonist Response In Asthma

 描述(由申请人提供)：监测试验表明，一类常见的吸入β2肾上腺素能受体激动剂(β激动剂)，长效β2肾上腺素能受体激动剂(LABA)1-3增加了危及生命的哮喘恶化的风险。相比之下，前瞻性随机试验表明，长效LABA与吸入皮质类固醇(ICS)联合使用可有效控制哮喘。30-32β2肾上腺素受体基因(ADRB2)中常见的编码单核苷酸多态性(SNP)的Gly16Arg调节对沙丁胺醇的反应，沙丁胺醇是一种短效β受体激动剂。但不是LABA。3-18对LABA的不良反应是罕见的，并且在不同种族之间的频率不同，因此，基于稀有变异的药物遗传学研究(等位基因频率和lt；0.05)或遗传血统，以解决LABA安全问题，并确定非洲裔美国人和非西班牙裔白人之间LABA反应差异的潜在机制。1，3，22-26 我们最近报道了一项对罕见ADRB2变体的研究，该研究表明，具有Ile164变体的非西班牙裔白人哮喘患者和具有罕见插入(-376 in-Del)的非西班牙裔美国人在LABA治疗期间严重恶化的风险增加。33我还使用全外显子测序数据评估了来自NHLBI重症哮喘研究计划(SARP)的191名非裔美国人，以确定与β激动剂反应相关的新的罕见基因座。34该建议的目标是验证以下假设，即来自不同种族的哮喘患者对吸入β激动剂的差异是由ADRB2内罕见的遗传变异、受体信号通路基因和整个基因组中的其他基因座决定的。 我们提出了三个具体目标来检验我的假设。目的：验证ADRB2和β2肾上腺素能受体(β2AR)信号通路中罕见变异对β激动剂治疗反应的影响。我们使用Illumina Human Exome BeadChip(Exome芯片)对来自SARP的1263名受试者和来自哮喘临床研究网络试验(ACRN)的377名受试者进行了基因分型。罕见的ADRB2变异将在1,614名非西班牙裔白人中进行基因分型；来自三项LABA-ICS临床试验的1,207名非洲裔美国人将被分型；以及500名非裔美国人的哮喘严重程度R01，其中包括正在进行的NHLBI哮喘网络试验。这1707名非洲裔美国人将用Illumina非洲散居人口电力芯片(“散居人口芯片”)进行基因分型。这些芯片涵盖了罕见的变异，并将构成验证ADRB2和通路基因的罕见变异对哮喘患者LABA反应的影响的研究。目的2：评估非洲血统和与非洲血统共同遗传的基因变异对非裔美国哮喘患者对β激动剂反应的影响。我将使用来自GWAS阵列的SNP，包括Diaspora芯片，用于这些哮喘队列中的非裔美国人的基于混合物的方法。我将评估全球非洲血统对 在使用LABA或SABA治疗期间的医疗保健利用率和肺功能，并通过精细作图执行混合作图以识别与β激动剂反应相关的基因座。目的3：在不同民族哮喘队列中识别与β激动剂反应相关的罕见变异的新基因座。我将结合基因分型芯片和全基因组方法的测序数据，在这些多民族哮喘队列中识别与β激动剂反应性相关的罕见变异的新基因座。 这些遗传学研究可以确定易受LABA治疗严重不良影响的哮喘患者的小而重要的亚群，同时阐明LABA反应的种族间差异的遗传基础。这些研究的1，22，27，28个基因变异可以构成不同种族群体中个性化哮喘管理方法的基因图谱。29该研究项目将得到分子医学研究生课程的补充，该课程将导致获得包括分子遗传学和人类疾病基因组学(MCB 742)、临床试验方法(CPTS 742)在内的博士学位，冷泉港实验室的两门基因分析课程和阿拉巴马大学的一门分析课程。这个多方面的职业发展计划将发生在世界级的指导和严格的临床试验经验的背景下，我在维克森林医学院基因组和个性化医学研究中心，网站NHLBI哮喘和SARP(博士ER Bleecker，SP彼得斯和DA Meyers)，并通过外部合作，从国家犹太人健康(ME Wechsler博士)和约翰霍普金斯大学(K Barnes博士)。该计划最终将提供经验和 我需要的培训，以达到我在临床试验、统计和功能基因组学以及复杂肺部疾病的药物遗传学方面的设计和伦理实施方面的专业知识的短期目标。这项计划还将使我走上一条通往我作为统计和功能基因组学领域的内科科学家独立的长期目标的道路。这份申请书包括：1)萨利·E·温泽尔医学博士；匹兹堡大学；2)威廉·W·布斯医学博士；威斯康星大学医学院；3)埃斯特班·冈萨雷斯·伯查德医学博士，公共卫生硕士；加州大学旧金山分校；4)埃利奥特·以色列医学博士；布里格姆和妇女医院；5)斯蒂芬·拉萨鲁斯医学博士；加州大学旧金山分校。

 DESCRIPTION (provided by applicant): Surveillance trials suggest that the risk for life-threatening asthma exacerbations are increased by a commonly prescribed class of inhaled beta2-adrenergic receptor agonists (beta agonists), the long-acting β2-adrenergic receptor agonists (LABA).1-3 In contrast, prospective randomized trials demonstrated that LABA effectively control asthma when combined with an inhaled corticosteroid (ICS).30-32 A common, coding single nucleotide polymorphism (SNP) in the β2-adrenergic receptor gene (ADRB2), Gly16Arg, modulates response to albuterol, a short-acting beta agonist (SABA), but not LABA.3-18 Adverse responses to LABA are rare and differ in frequency between ethnic groups, thus, pharmacogenetic studies based on rare variants (allele frequency < 0.05) or genetic ancestry are needed to address the LABA safety issue and identify mechanisms underlying differences in LABA response between African Americans and non-Hispanic Whites.1,3,22-26 We recently reported a study of rare ADRB2 variants demonstrating that non-Hispanic White asthmatics with the Ile164 variant and African Americans with a rare insertion (-376 In-Del) had an increased risk for severe exacerbations during LABA treatment.33 I also evaluated 191 African Americans from the NHLBI Severe Asthma Research Program (SARP) with whole-exome sequencing data to identify novel rare loci associated with beta agonist response.34 The goal of this proposal is to test the hypothesis that differential responses to inhaled beta agonists among asthmatics from different ethnic groups is determined by rare genetic variation within ADRB2, receptor signaling pathway genes, and additional loci throughout the genome. We propose three specific aims to test my hypothesis. Aim 1: To validate the effects of rare variants within ADRB2 and the β2-adrenergic receptor (β2AR) signaling pathway on response to beta agonist therapy. We have genotyped 1,263 subjects from SARP and 377 subjects from Asthma Clinical Research Network trials (ACRN) with the Illumina HumanExome BeadChip ("Exome Chip"). Rare ADRB2 variants will be genotyped in 1,614 non-Hispanic Whites; 1,207 African Americans from three LABA-ICS clinical trials, including an ongoing NHLBI AsthmaNet trial; and 500 African Americans from an R01 of asthma severity. These 1,707 African Americans will be genotyped with the Illumina African Diaspora Power Chip ("Diaspora Chip"). These chips cover rare variants and will constitute studies to validate the effects of rare variants in ADRB2 and pathway genes on LABA response in asthmatics. Aim 2: To assess the effects of African ancestry and genetic variants co-inherited with African ancestry on the response to beta agonists in African American asthmatics. I will use SNPs from GWAS arrays, including the Diaspora Chip, for admixture-based approaches in African Americans from these asthma cohorts. I will evaluate the effect of global African ancestry on healthcare utilization and lung function during treatment with LABA or SABA and perform admixture mapping with fine mapping to identify loci associated with beta agonist response. Aim 3: To identify novel loci with rare variants associated with response to beta agonists in different ethnic asthma cohorts. I will integrate genotyping chip and sequencing data for whole-genome methods to identify novel loci with rare variants associated with beta agonist responsiveness in these multi-ethnic asthma cohorts. These genetic studies could define the small, important subgroup of asthmatics susceptible to severe, adverse effects of LABA therapy while elucidating the genetic basis for inter-ethnic differences in LABA responsiveness.1,22,27,28 Genetic variants from these studies could constitute genetic profiles for personalized approaches for the management of asthma in different ethnic groups.29 This research project will be complemented by graduate coursework in Molecular Medicine that will lead to a PhD including Molecular Genetics and Genomics of Human Disease (MCB 742), Clinical trials methods (CPTS 742), two genetic analytical course at the Cold Springs Harbor Laboratory, and one analytical course at the University of Alabama. This multi-faceted career development plan will occur in the context of the world-class mentoring and rigorous clinical trials experience available to me at the Wake Forest School of Medicine Center for Genomics and Personalized Medicine Research, site for NHLBI AsthmaNet and SARP, (Drs. ER Bleecker, SP Peters, and DA Meyers) and through outside collaboration with experts from National Jewish Health (Dr. ME Wechsler) and Johns Hopkins University (Dr. K Barnes). This plan will ultimately provide the experience and training which I require to reach my short-term goals of expertise in the design and ethical implementation of clinical trials, statistical and functional genomics, and the pharmacogenetics of complex lung disease. This plan will also set me on a path towards my long-term goal of independence as a physician-scientist in the fields of statistical and functional genomics. This application includes letters of support from: 1) Sally E. Wenzel, MD; University of Pittsburgh; 2) William W. Busse, MD; University of Wisconsin School of Medicine; 3) Esteban Gonzalez Burchard, MD, MPH; University of California, San Francisco; 4) Elliot Israel, MD; Brigham and Women's Hospital; 5) Stephan Lazarus, MD; University of California, San Francisco.