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: 8968045
• 负责人: Victor E. Ortega
• 金额: $ 11.76万
• 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/8968045
• 关键词: ADRB2 gene; Address; Admixture; Adrenal Cortex Hormones; Adrenergic Agonists; Adrenergic Receptor; 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 Pathway Gene; Single Nucleotide Polymorphism; Site; Subgroup; Testing; Therapeutic; Training; Treatment Failure; United States Food and Drug Administration; Universities; Variant; Wisconsin; Woman; asthmatic; base; bead chip; 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 genomic medicine; post-market; prevent; programs; prospective; public health relevance; randomized trial; rare variant; receptor binding; response; safety study

 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（申请人提供）：监测试验表明，一种常用的吸入性β 2-肾上腺素能受体激动剂会增加危及生命的哮喘急性发作的风险（β激动剂），长效β2-肾上腺素能受体激动剂（LABA）。1 -3相反，前瞻性随机试验表明，当LABA与吸入性皮质类固醇（ICS）联合使用时，β2-肾上腺素能受体基因（ADRB 2）Gly 16 Arg编码单核苷酸多态性（SNP）调节对沙丁胺醇（一种短效β激动剂（SABA））的反应，但不调节对LABA的反应。3 -18对LABA的不良反应很罕见，并且在种族群体之间的频率不同，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安全性问题，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。 我们最近报道了一项关于罕见ADRB 2变异的研究，表明携带Ile 164变异的非西班牙裔白色哮喘患者和携带罕见插入的非裔美国人（-376 In-Del）在LABA治疗期间严重急性发作的风险增加。33我还评估了来自NHLBI严重哮喘研究项目（SARP）的191名非裔美国人，外显子组测序数据用于识别与β受体激动剂反应相关的新型罕见基因座。34本提案的目标是检验以下假设：不同种族哮喘患者对吸入β受体激动剂的差异反应是由ADRB 2内的罕见遗传变异决定的，受体信号传导途径基因和整个基因组中的其他基因座。 我们提出三个具体目标来检验我的假设。目标1：验证ADRB 2和β2-肾上腺素能受体（β2AR）信号通路中罕见变体对β受体激动剂治疗反应的影响。 我们用Illumina HumanExome BeadChip（“外显子组芯片”）对来自SARP的1，263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ADRB 2变异体将在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，包括正在进行的NHLBI AsthmaNet试验;以及来自R 01哮喘严重程度的500名非洲裔美国人。这1，707名非裔美国人将使用Illumina African Diaspora Power Chip（“Diaspora Chip”）进行基因分型。这些芯片涵盖了罕见变异，并将构成研究，以验证ADRB 2和途径基因中罕见变异对哮喘患者LABA反应的影响。目标二：评估非洲血统和与非洲血统共同遗传的遗传变异对非裔美国人哮喘患者对β受体激动剂反应的影响。我将使用来自GWAS阵列的SNP，包括Diaspora芯片，在这些哮喘队列的非裔美国人中进行基于混合物的方法。我将评估全球非洲血统对 在用LABA或SABA治疗期间的医疗保健利用和肺功能，并进行具有精细定位的混合物定位以鉴定与β激动剂反应相关的基因座。目的3：在不同种族哮喘人群中鉴定与β受体激动剂反应相关的罕见变异的新基因座。我将整合全基因组方法的基因分型芯片和测序数据，以确定这些多种族哮喘队列中与β激动剂反应相关的罕见变异的新位点。 这些遗传学研究可以确定对LABA治疗的严重不良反应敏感的小而重要的哮喘患者亚组，同时阐明LABA反应性种族间差异的遗传基础。1，22，27，28这些研究的遗传变异可以构成不同种族群体哮喘管理个性化方法的遗传谱。29该研究项目将由研究生补充在分子医学课程，将导致博士学位，包括分子遗传学和人类疾病的基因组学（MCB 742），临床试验方法（CPTS 742），在冷泉港实验室的两个遗传分析课程，并在亚拉巴马大学的一个分析课程。这个多方面的职业发展计划将发生在世界一流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学和个性化医学研究中心，网站为NHLBI AsthmaNet和SARP，（ER Bleecker、SP Peters、和DA Meyers），并通过与国家犹太健康（ME Wechsler博士）和约翰霍普金斯大学（K巴恩斯博士）的专家进行外部合作。该计划最终将提供经验， 培训，我需要达到我的专业知识的设计和临床试验，统计和功能基因组学的伦理实施的短期目标，以及复杂的肺部疾病的药物遗传学。这个计划也将使我走上一条通往我作为统计和功能基因组学领域的医生科学家独立的长期目标的道路。此应用程序包括支持信：1）莎莉E。温泽尔，医学博士;匹兹堡大学; 2）威廉W。Busse，MD;威斯康星州大学医学院; 3）Esteban Gonzalez Burchard，医学博士，公共卫生硕士;加州大学旧金山分校; 4）Elliot Israel，医学博士; Brigham and Women's Hospital; 5）Stephan Lazarus，医学博士;加州大学旧金山分校弗朗西斯科。