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.

总结 监测试验表明，危及生命的哮喘急性发作和哮喘相关死亡的风险 长效β2-肾上腺素能受体（β2AR）激动剂（LABA）治疗增加，尽管前瞻性 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， 与吸入性皮质类固醇（ICS）联合使用。尽管如此，不良结局和治疗的风险 与白人相比，非裔美国人在LABA治疗期间的失败率更高。我们已经证明， β2-肾上腺素能受体基因（ADRB 2）的遗传变异与哮喘急性发作相关 受试者服用LABA。我们还表明，非洲血统与下肺 在患有严重哮喘和COPD的非裔美国人中的功能。这些数据为使用 传统的和功能性的遗传学方法来阐明祖先特异性遗传变异的作用， 包括β2AR信号通路重要组分的新变体和变异， β激动剂反应和肺功能。我们假设种族特异性遗传变异，特别是 罕见变异和β2AR途径变异，对β激动剂反应有重要影响， 基线肺功能。我们提出了以下具体目标：目标1：确定新的遗传 多种族哮喘患者与β受体激动剂反应相关的变异和肺功能测量 和COPD队列，使用基于罕见变异体、基于混合物的全基因组 分析和GWAS。我们将利用现有的综合基因分型与插补和下一步- SARP 1 -3中1，919例哮喘受试者的世代测序（NGS）数据集，哮喘研究中839例受试者的世代测序（NGS）数据集 临床研究网络试验，2，807例（1，122例非裔/非裔美国人和554例西班牙裔）哮喘受试者 来自三项LABA-ICS临床试验和2，507名SPIROMICS受试者，用于发现新的基因通路 与β受体激动剂反应和肺功能有关。目的2：验证变量在 β2-肾上腺素能受体（β 2-AR）通路和β激动剂反应与肺的新基因通路 在多种族β受体激动剂治疗的临床试验队列中发挥作用。我们将在40个样本上重新执行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， 鉴定构成β激动剂反应和肺的预测性遗传谱的新基因-基因相互作用 目的3：验证β 2 AR中罕见变异的生物学效应。 信号通路，以完善和支持β激动剂治疗的遗传预测谱 响应能力。β2AR途径罕见变异将通过分子表型进行评价，以细化 预测基因图谱拟议的研究有可能定义以下风险亚组： 哮喘易受LABA治疗不良反应的影响，同时确定β激动剂的新位点 反应或疾病的严重程度，并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

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

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