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

罕见变异和祖先对哮喘β受体激动剂反应的影响

• 批准号: 9098841
• 负责人: Victor E. Ortega
• 金额: $ 14.99万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098841
• 关键词: ADRB2 gene; Address; Admixture; Adrenal Cortex Hormones; Adrenergic Agonists; Adverse effects; African; African American; Agonist; Alabama; Albuterol; Asthma; Boxing; Breathing; Bronchodilator Agents; California; Cessation of life; ChIP-seq; Clinical Research; Clinical Trials; Code; Collaborations; Complement; Complex; Data; Development Plans; Doctor of Philosophy; Ethics; Ethnic group; Frequencies; Gene Frequency; General Population; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; Health; Hospitals; Inherited; Israel; Laboratories; Lead; Letters; Life; Lung diseases; Maps; Mentors; Methods; Molecular Genetics; Molecular Medicine; National Heart, Lung, and Blood Institute; Not Hispanic or Latino; Pathway interactions; Patients; Pharmacogenetics; Physicians; Play; Public Health; Receptor Gene; Receptor Signaling; Reporting; Research; Research Project Grants; Respiratory physiology; Risk; Role; Safety; San Francisco; Scientist; Severities; Signal Pathway; Signaling Protein; Single Nucleotide Polymorphism; Site; Subgroup; Testing; Therapeutic; Training; Treatment Failure; United States Food and Drug Administration; Universities; Variant; Wisconsin; Woman; admixture mapping; asthmatic; base; bead chip; beta-2 Adrenergic Receptors; career development; cohort; design; ethnic difference; exome; exome sequencing; experience; follower of religion Jewish; forest; functional genomics; genetic profiling; genetic variant; genome wide association study; health care service utilization; human disease; improved; medical schools; novel; personalized approach; personalized genomic medicine; post-market; prevent; programs; prospective; randomized trial; rare variant; receptor binding; response; safety study; treatment response; whole genome

 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.

 描述（由申请人提供）：监测试验表明，常用的一类吸入性 β2 肾上腺素受体激动剂（β 激动剂），即长效 β2 肾上腺素受体激动剂 (LABA)，会增加危及生命的哮喘急性发作的风险。 .1-3 相反，前瞻性随机试验表明，LABA 与吸入皮质类固醇 (ICS) 联合使用可有效控制哮喘。30-32 β2 肾上腺素能受体基因 (ADRB2) 中常见的编码单核苷酸多态性 (SNP) Gly16Arg 可调节对沙丁胺醇（一种短效 β 激动剂 (SABA)）的反应，但不能调节 LABA。3-18 对 LABA 的不良反应是种族间的罕见且频率不同，因此，需要基于罕见变异（等位基因频率 < 0.05）或遗传祖先的药物遗传学研究来解决LABA 安全问题并确定非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关于罕见 ADRB2 的研究，表明具有 Ile164 变异体的非西班牙裔白人哮喘患者和具有罕见插入 (-376 In-Del) 的非裔美国人在 LABA 治疗期间严重恶化的风险增加。 33 我还评估了 191 NHLBI 严重哮喘研究计划 (SARP) 的非裔美国人利用全外显子组测序数据来识别与 β 激动剂反应相关的新型罕见位点。 34 该提案的目标目的是检验以下假设：不同种族的哮喘患者对吸入 β 受体激动剂的差异反应是由 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。目标 1：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。我们对来自 SARP 的 1,263 名受试者和 377 名受试者进行了基因分型。来自哮喘临床研究网络 (ACRN) 的 Illumina HumanExome BeadChip（“外显子组芯片”）试验将在 2017 年进行罕见 ADRB2 变体的基因分型。 1,614 名非西班牙裔白人；来自三项 LABA-ICS 临床试验的 1,207 名非裔美国人，包括正在进行的 NHLBI AsthmaNet 试验；以及来自 R01 哮喘严重程度的 500 名非裔美国人，这 1,707 名非裔美国人将使用 Illumina 非洲侨民 Power 芯片进行基因分型。 “Diaspora Chip”）。这些芯片涵盖罕见变异，并将构成研究以验证 ADRB2 和途径基因中罕见变异的影响。目标 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（包括 Diaspora Chip）的 SNP 进行混合。我将评估全球非洲血统对非裔美国人哮喘人群的影响。 目的 3：识别不同种族哮喘人群中与 β 激动剂反应相关的罕见变异的新基因座。将整合基因分型芯片和全基因组方法的测序数据，以确定这些多种族哮喘队列中与β受体激动剂反应性相关的罕见变异的新位点。 这些基因研究可以定义易受 LABA 治疗严重不良反应影响的小而重要的哮喘患者亚群，同时阐明 LABA 反应性的种族间差异的遗传基础。1,22,27,28 这些研究中的遗传变异可能构成遗传性29 该研究项目将得到分子医学研究生课程的补充，该课程将获得包括人类疾病分子遗传学和基因组学 (MCB) 在内的博士学位742）、临床试验方法（CPTS 742）、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。这一多方面的职业发展计划将在世界一流的指导背景下进行。我在维克森林大学医学院基因组学和个性化医学研究中心、NHLBI AsthmaNet 和 SARP 网站（ER Bleecker 博士、SP Peters 和 DA Meyers 博士）获得了严格的临床试验经验，通过与国家犹太健康中心（ME Wechsler 博士）和约翰·霍普金斯大学（K Barnes 博士）的专家的外部合作，该计划最终将提供经验和经验。 我需要接受培训，以实现临床试验的设计和伦理实施、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专业知识的短期目标。该计划也将使我走上一条通往长期的道路。作为统计和功能基因组学领域的医师科学家的独立目标本申请包括来自以下机构的支持信：1) 匹兹堡大学 Sally E. Wenzel；2) 威斯康星大学 William W. Busse；医学院； 3) Esteban Gonzalez Burchard，医学博士，公共卫生硕士；4) Elliot Israel，医学博士；5) Stephan Lazarus，医学博士，旧金山；