Genetic studies in difficult to treat asthma: TENOR

难治性哮喘的基因研究：TENOR

• 批准号: 7254057
• 负责人: EUGENE ROLAND BLEECKER
• 金额: $ 53.36万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254057
• 关键词: ADRB2 gene; ARHGEF5 gene; Academy; Acute; Adrenal Cortex Hormones; Adrenergic Agents; Adrenergic Receptor; Adult; Affect; Affinity; African American; Agonist; Albuterol; Alleles; Allergic; American; Anti-Inflammatory Agents; Anti-inflammatory; Arginine; Asians; Asthma; Blood; Breathing; Bronchodilator Agents; CD14 gene; CD28 gene; CTLA4 gene; Caring; Case-Control Studies; Cell physiology; Characteristics; Chest; Child; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Cohort Studies; Collection; Commit; Communities; Contracts; DNA; Data; Data Analyses; Databases; Disease; Dose; Education; Elements; Enrollment; Environmental Risk Factor; Epidemiologist; Epidemiology; Ethnic Origin; Fibrinogen; Frequencies; Funding; Future; Gelatinase B; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genomics; Genotype; Glucocorticoid Receptor; Glucocorticoids; Glycine; Grant; Guidelines; Haplotypes; Health Maintenance Organizations; Healthcare; High Prevalence; Hispanics; Homozygote; Hospitals; Human Resources; Hypersensitivity; IL4 gene; IL4R gene; IgE; IgE Receptors; Immunology; Inflammation; Inflammatory Response; Informed Consent; Interleukin-13; Interleukin-4; Investigation; Israel; Label; Laboratories; Letters; Leukotrienes; MMP9 gene; Managed Care; Measures; Mediation; Methods; Minority; Morbidity - disease rate; Natural History; Numbers; Outcome; Pacific Island Americans; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patients; Pattern; Peak Expiratory Flow Rate; Pharmaceutical Preparations; Pharmacogenetics; Pharmacologic Substance; Phenotype; Physicians; Population; Population Study; Positioning Attribute; Prevention program; Process; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Quality of life; Questionnaires; Receptor Gene; Recording of previous events; Regulation; Reporting; Research Ethics Committees; Research Personnel; Resources; Respiratory physiology; Response Elements; Risk; Salmeterol; Sampling; Schedule; Serum; Severities; Shipping; Ships; Single Nucleotide Polymorphism; Societies; Spirometry; Symptoms; TLR4 gene; TNF gene; Testing; Time; Tissues; Treatment Protocols; Treatment outcome; United States; United States National Institutes of Health; Universities; Variant; Visit; adrenergic; aged; airway inflammation; airway remodeling; arginylarginine; asthma inhaler; base; beta-2 Adrenergic Receptors; cost; cytokine; data management; environmental agent; forest; formoterol; genetic association; health care service utilization; injury and repair; programs; prospective; pulmonary function; receptor; response

DESCRIPTION (provided by applicant): The TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) study is an ongoing three-year multi-center observational cohort study of 4756 severe or difficult-to-treat patients with asthma aged 6 or older. Of this group of asthmatics, 44.6% meet the NHLBI NAEPP guidelines for severe persistent asthma, 27.5% for moderate persistent asthma, and 27.8% for mild persistent asthma. All subjects were evaluated initially with comprehensive questionnaires and laboratory testing, and are then seen every 6 months during the remaining 3 years of the study. Phenotypic information collected includes information on asthma exacerbations, medication use, urgent care visits, quality of life, pulmonary function tests (spirometry with reversibility), total serum IgE levels, and history of allergies. If accessed now, before the termination of the TENOR study, this population represents one of the largest populations of phenotypically characterized difficult-to-treat and severe asthmatics potentially available for genomic and pharmacogenetic studies. TENOR will finish at the end of 2004, thus we have a very short time window in which to obtain DNA samples for genetic studies before the termination of the study. Isolation and storage of DNA from this well characterized, longitudinal population will serve as a resource not only for the proposed studies in this grant but also for future genomics and pharmacogenetic studies in asthma. We propose to investigate genetic factors that affect asthma severity in this well-characterized, large asthma population. We hypothesize that factors which produce difficult-to-treat and severe asthma are produced by altered inflammatory responses that are related, at least in part, to sequence variants (polymorphisms) in genes that regulate inflammation, allergic responsiveness, and/or affect structural components in the airways. We also hypothesize that some patients develop more severe asthma because of genetic differences that modulate their responses to pharmacologic agents. To test these hypotheses, we propose the following specific aims: 1) Obtain DNA samples from at least 4,000 asthmatics currently enrolled in the ongoing TENOR study; 2) Determine whether sequence variants (polymorphisms) in genes that regulate inflammation, cellular responses, and/or tissue injury and repair are more frequently associated with asthma severity using the baseline data; 3) Determine the importance of genetic polymorphisms in genes that may be important in IgE regulation in this population of difficult-to-treat patients with asthma; 4) Evaluate pharmacogenetic relationships between polymorphisms in the ¿2 adrenergic receptor (¿2AR) in those subjects on long-acting beta-2-agonists to determine the effect on asthma severity; 5) Evaluate pharmacologic mechanisms by investigating whether polymorphisms in genes that regulate responses to asthma therapy are more frequent in severe disease.

描述（由申请人提供）：TENOR（哮喘的流行病学和自然史：结局和治疗方案）研究是一项正在进行的为期3年的多中心观察性队列研究，纳入4756例6岁或以上重度或难以治疗的哮喘患者。在这组哮喘患者中，44.6%符合NHLBI NAEPP重度持续性哮喘指南，27.5%符合中度持续性哮喘，27.8%符合轻度持续性哮喘。所有受试者最初都接受了综合问卷调查和实验室检查，然后在研究的剩余3年中每6个月进行一次观察。收集的表型信息包括哮喘急性发作、药物使用、紧急护理访视、生活质量、肺功能检查（可逆性肺功能测定）、总血清IgE水平和过敏史。如果在TENOR研究终止之前现在进行访问，该人群代表了可能可用于基因组和药物遗传学研究的表型特征难以治疗和严重哮喘患者的最大人群之一。TENOR研究将于2004年年底完成，因此，在研究结束前，我们有一个很短的时间窗口来获取DNA样本进行遗传研究。从这一特征良好的纵向人群中分离和储存DNA不仅将作为本基金中拟议研究的资源，也将作为未来哮喘基因组学和药物遗传学研究的资源。我们建议在这个特征明确的大规模哮喘人群中调查影响哮喘严重程度的遗传因素。我们假设，产生难以治疗和严重哮喘的因素是由改变的炎症反应产生的，这些炎症反应至少部分与调节炎症、过敏反应和/或影响气道结构成分的基因序列变异（多态性）有关。我们还假设，一些患者发展为更严重的哮喘，因为遗传差异，调节他们对药物的反应。为了验证这些假设，我们提出了以下具体目标：1）从目前正在进行的TENOR研究中招募的至少4，000名哮喘患者中获得DNA样本; 2）确定序列变异是否使用基线数据，调节炎症、细胞反应和/或组织损伤和修复的基因中的多态性更频繁地与哮喘严重程度相关; 3）确定在难治性哮喘患者人群中可能对IgE调节重要的基因中遗传多态性的重要性; 4）评估<$2肾上腺素能受体（<$2）多态性与哮喘患者的遗传易感性之间的药物遗传学关系。2 AR），以确定对哮喘严重程度的影响; 5）通过研究调节哮喘治疗反应的基因多态性是否在严重疾病中更常见，评估药理学机制。

项目成果

Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort.

• DOI: 10.1007/s13665-012-0025-x
• 发表时间: 2012-12
• 期刊: Current respiratory care reports
• 作者: Chipps BE;Zeiger RS;Dorenbaum A;Borish L;Wenzel SE;Miller DP;Hayden ML;Bleecker ER;Simons FE;Szefler SJ;Weiss ST;Haselkorn T;TENOR Study Group
• 通讯作者: TENOR Study Group

Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions.

• DOI: 10.1016/j.jaci.2009.11.018
• 发表时间: 2010-02
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Li, Xingnan;Howard, Timothy D.;Zheng, Siqun L.;Haselkorn, Tmirah;Peters, Stephen P.;Meyers, Deborah A.;Bleecker, Eugene R.
• 通讯作者: Bleecker, Eugene R.

Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma.

• DOI: 10.1111/all.12990
• 发表时间: 2016-12
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Nieuwenhuis MA;Siedlinski M;van den Berge M;Granell R;Li X;Niens M;van der Vlies P;Altmüller J;Nürnberg P;Kerkhof M;van Schayck OC;Riemersma RA;van der Molen T;de Monchy JG;Bossé Y;Sandford A;Bruijnzeel-Koomen CA;Gerth van Wijk R;Ten Hacken NH;Timens W;Boezen HM;Henderson J;Kabesch M;Vonk JM;Postma DS;Koppelman GH
• 通讯作者: Koppelman GH

Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study.

• DOI: 10.1016/j.jaci.2012.04.014
• 发表时间: 2012-08
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Chipps, Bradley E.;Zeiger, Robert S.;Borish, Larry;Wenzel, Sally E.;Yegin, Ashley;Hayden, Mary Lou;Miller, Dave P.;Bleecker, Eugene R.;Simons, F. Estelle R.;Szefler, Stanley J.;Weiss, Scott T.;Haselkorn, Tmirah
• 通讯作者: Haselkorn, Tmirah