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: 10620284
• 负责人: Victor E. Ortega
• 金额: $ 67.41万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620284
• 关键词: ADRB2 gene; Admixture; Adrenal Cortex Hormones; Adrenergic Agonists; 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; Ethnic Origin; Ethnic Population; 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; Predisposition; Receptor Gene; Reporting; Research; Risk; Role; Safety; Severity of illness; Signal Pathway; Subgroup; Therapeutic; Treatment Failure; Variant; Weight; admixture mapping; adverse outcome; asthma exacerbation; 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 监视试验表明，威胁生命的哮喘患者和与哮喘有关的死亡的风险 长效β2-肾上腺素受体（β2AR）激动剂（LABA）疗法增加，尽管前瞻性 当Laba时，包括FDA规定的安全研究在内的随机试验尚未证实这些观察结果 与遗传性皮质类固醇（ICS）结合使用。尽管如此，不良后果和治疗的风险 与白人相比，非裔美国人的LABA治疗期间失败更高。我们已经表明了罕见 β2-肾上腺素受体基因（ADRB2）中的遗传变异与哮喘的恶化有关 受试者服用Labas。我们还表明，非洲血统与下肺密切相关 严重哮喘和COPD的非裔美国人的功能。这些数据提供了强大的理由 常规和功能性遗传方法阐明了祖先特异性遗传变异的作用， 包括新的变体和β2AR信号通路的重要组成部分的变化，以确定 β激动剂反应和肺功能。我们假设种族特异性的遗传变异，特别是 稀有变体和β2AR途径变化，对β激动剂反应和 基线肺功能。我们提出以下特定目的：目标1：确定新的遗传 与β激动剂反应相关的变体和多种族哮喘中肺功能的度量 和COPD队列，结合了稀有的基于混合的混合物的全基因组 分析和GWAS。我们将利用现有的综合基因分型和下一步 来自SARP1-3的1,919名哮喘受试者的生成测序（NGS）数据集，来自哮喘的839名受试者 临床研究网络试验，2,807（1,122名非洲/非裔美国人和554个西班牙裔）哮喘科目 从三个Laba-ICS临床试验和2,507个螺旋学受试者发现新型基因途径 与β激动剂反应和肺功能相关。目标2：验证变体在 β2-肾上腺素能受体（β2AR）途径和新的基因途径在β激动剂反应和肺 多种族β激动剂处理的临床试验队列中的功能。我们将在40上进行从头执行。 β2AR途径基因并利用现有的全基因组测序数据进行β2AR途径分析到 确定构成β激动剂反应和肺的预测遗传特征的新型基因基因相互作用 跨种族的功能.AIM 3：验证β2AR内稀有变体的生物学效应 信号通路以完善和支持β激动剂疗法的遗传预测概况 响应能力。 β2AR途径罕见变化将通过分子表型进行评估 预测遗传谱。拟议的研究有可能定义一个处于危险的亚组 哮喘容易受到LABA疗法的不良影响，同时识别新型β激动剂的局部 反应或疾病的严重程度以及阐明种族间差异的新机制。

项目成果

A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts.

来自六个独立队列的欧洲和非洲血统参与者的支气管扩张剂反应的全基因组关联研究。

• DOI: 10.1183/23120541.00484-2021
• 发表时间: 2022
• 期刊: ERJ open research
• 影响因子: 4.6
• 作者: Gereige,JessicaD;Xu,Hanfei;Ortega,VictorE;Cho,MichaelH;Liu,Ming;Sakornsakolpat,Phuwanat;Silverman,EdwinK;Beaty,TerriH;Miller,BruceE;Bakke,Per;Gulsvik,Amund;Hersh,CraigP;Morrow,JarrettD;InternationalCOPDGeneticsConsorti
• 通讯作者: InternationalCOPDGeneticsConsorti

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma.

• DOI: 10.1016/s2352-4642(21)00268-6
• 发表时间: 2021-12
• 期刊: The Lancet. Child & adolescent health
• 作者: Ortega VE;Daya M;Szefler SJ;Bleecker ER;Chinchilli VM;Phipatanakul W;Mauger D;Martinez FD;Herrera-Luis E;Pino-Yanes M;Hawkins GA;Ampleford EJ;Kunselman SJ;Cox C;Bacharier LB;Cabana MD;Cardet JC;Castro M;Denlinger LC;Eng C;Fitzpatrick AM;Holguin F;Hu D;Jackson DJ;Jarjour N;Kraft M;Krishnan JA;Lazarus SC;Lemanske RF Jr;Lima JJ;Lugogo N;Mak A;Moore WC;Naureckas ET;Peters SP;Pongracic JA;Sajuthi SP;Seibold MA;Smith LJ;Solway J;Sorkness CA;Wenzel S;White SR;Burchard EG;Barnes K;Meyers DA;Israel E;Wechsler ME;NHLBI AsthmaNet
• 通讯作者: NHLBI AsthmaNet

Multi-ancestry genome-wide association study of asthma exacerbations.

• DOI: 10.1111/pai.13802
• 发表时间: 2022-06
• 期刊: PEDIATRIC ALLERGY AND IMMUNOLOGY
• 影响因子: 4.4
• 作者: Herrera-Luis, Esther;Ortega, Victor E.;Ampleford, Elizabeth J.;Sio, Yang Yie;Granell, Raquel;de Roos, Emmely;Terzikhan, Natalie;Vergara, Ernesto Elorduy;Hernandez-Pacheco, Natalia;Perez-Garcia, Javier;Martin-Gonzalez, Elena;Lorenzo-Diaz, Fabian;Hashimoto, Simone;Brinkman, Paul;Jorgensen, Andrea L.;Yan, Qi;Forno, Erick;Vijverberg, Susanne J.;Lethem, Ryan;Espuela-Ortiz, Antonio;Gorenjak, Mario;Eng, Celeste;Gonzalez-Perez, Ruperto;Hernandez-Perez, Jose M.;Poza-Guedes, Paloma;Sardon, Olaia;Corcuera, Paula;Hawkins, Greg A.;Marsico, Annalisa;Bahmer, Thomas;Rabe, Klaus F.;Hansen, Gesine;Kopp, Matthias Volkmar;Rios, Raimon;Cruz, Maria Jesus;Gonzalez-Barcala, Francisco-Javier;Maria Olaguibel, Jose;Plaza, Vicente;Quirce, Santiago;Canino, Glorisa;Cloutier, Michelle;Del Pozo, Victoria;Rodriguez-Santana, Jose R.;Korta-Murua, Javier;Villar, Jesus;Potocnik, Uros;Figueiredo, Camila;Kabesch, Michael;Mukhopadhyay, Somnath;Pirmohamed, Munir;Hawcutt, Daniel B.;Melen, Erik;Palmer, Colin N.;Turner, Steve;Maitland-van der Zee, Anke H.;von Mutius, Erika;Celedon, Juan C.;Brusselle, Guy;Chew, Fook Tim;Bleecker, Eugene;Meyers, Deborah;Burchard, Esteban G.;Pino-Yanes, Maria
• 通讯作者: Pino-Yanes, Maria

FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease.

• DOI: 10.1136/bmjresp-2020-000714
• 发表时间: 2020-11
• 期刊: BMJ open respiratory research
• 影响因子: 4.1
• 作者: Alderawi A;Caramori G;Baker EH;Hitchings AW;Rahman I;Rossios C;Adcock I;Cassolari P;Papi A;Ortega VE;Curtis JL;Dunmore S;Kirkham P
• 通讯作者: Kirkham P

DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program.

• DOI: 10.1002/ppul.25939
• 发表时间: 2022-07
• 期刊: PEDIATRIC PULMONOLOGY
• 影响因子: 3.1
• 作者: Izquierdo, Manuel E.;Marion, Chad R.;Moore, Wendy C.;Raraigh, Karen S.;Taylor-Cousar, Jennifer L.;Cutting, Gary R.;Ampleford, E.;Hawkins, Gregory A.;Zein, Joe;Castro, M.;Denlinger, Loren C.;Erzurum, Serpil C.;Fahy, John, V;Israel, Elliot;Jarjour, Nizar N.;Mauger, David;Levy, Bruce D.;Wenzel, Sally E.;Woodruff, Prescott;Bleecker, Eugene R.;Meyers, Deborah A.;Ortega, Victor E.
• 通讯作者: Ortega, Victor E.