Polymorphisms of Neural NOS and the Asthma Phenotype

神经 NOS 多态性与哮喘表型

• 批准号: 6906454
• 负责人: MICHAEL E WECHSLER
• 金额: $ 13.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-05 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906454
• 关键词: asthma; genetic polymorphism; genetic susceptibility; human subject; nitric oxide; nitric oxide synthase; nucleic acid repetitive sequence; patient oriented research; respiratory gas level; respiratory hypersensitivity

DESCRIPTION (provided by applicant) Nitric oxide (NO) is a potent bioactive mediator that has been implicated in the pathogenesis of asthma as it has been noted to have both proinflammatory and bronchodilatory effects. Clinically, it is well established that levels of mixed expired NO are, on average, considerably higher in patients with asthma than in nonasthmatics. However, a wide spectrum of heterogeneity exists among asthmatics in terms of levels of expired NO. NO is formed in the lung by a family of enzymes known as the nitric oxide synthases, and allelic variations of NOS1, the gene for neural nitric oxide synthase (type I NOS) on chromosome l2q, have been identified and associated with asthma. Animal studies have documented that targeted disruption of NOS1 resulted in lower levels of exhaled NO and decreased airway hyperresponsiveness following allergen challenge, thus demonstrating the potential importance of NOS1 in asthma pathogenesis. A potential role of NOS1 in asthma pathogenesis and heritability derives from the fact that one of the recently described NOS1 polymorphisms consists of intronic trinucleotide tandem repeats that are similar to the repeat sequences that have been implicated in the pathogenesis of several neurologic disorders including Huntington?s Disease. Preliminary human studies reviewed herein suggest that mild asthmatics who harbor NOS1 alleles with a greater number of intronic trinucleotide repeats have lower and less variable levels of expired NO. This association has been replicated in patients with cystic fibrosis. These observations prompt the following hypothesis: Polymorphisms of NOS1 are associated with variable levels of exhaled NO and airway hyperresponsiveness in subjects with asthma; these allelic variations in NOS1 with resultant variable NO production manifest as significant distinct asthma phenotypes with variable clinical features representing important clues to the genetic diversity of asthma. To test this hypothesis, we propose three specific aims. In the first specific aim, we will determine the relationship between genotype at the NOS1 locus, baseline lung function and mixed expired NO in a cohort of patients with mild-to-moderate asthma. If our hypothesis is correct, we expect to demonstrate that asthmatics harboring allelic variants with greater number of repeats excrete less NO in their exhaled breath and are relatively hyporesponsive to non-specific bronchoprovocative maneuvers as compared to asthmatics with similar clinical characteristics whose alleles harbor fewer repeats. In the next two specific aims, we will study the response of a cohort of subjects with asthma with different NOS1 polymorphisms to specific clinical interventions, including bronchoprovocation with allergen inhalation, bradykinin challenge, hypertonic saline challenge and withdrawal of inhaled corticosteroids. We expect to demonstrate that subjects harboring different NOS1 alleles will have differential responses to these various challenges. We hope that completion of these specific aims will help us understand the role of nitric oxide as a mediator and indicator of asthmatic airway inflammation, how genetic differences influence these roles, and how neural mechanisms may contribute to the pathophysiology and symptomatology of asthma.

描述（由申请人提供） 一氧化氮（NO）是一种有效的生物活性介质， 哮喘的发病机制，因为它已被注意到，既有促炎性 和支气管扩张作用。在临床上，已经确定， 平均而言，哮喘患者的混合呼气NO显著较高， 而不是哮喘患者。然而，存在着广泛的异质性， 哮喘患者在呼出的NO水平方面。NO在肺中由一种 被称为一氧化氮合酶的酶家族，以及等位基因变异 NOS 1，染色体上的神经型一氧化氮合酶（I型NOS）基因 l2 q已被确定并与哮喘相关。动物研究 有记录表明，有针对性的破坏NOS 1导致较低水平的 呼出的NO和降低过敏原后的气道高反应性 挑战，从而证明了NOS 1在哮喘中的潜在重要性 发病机制一氧化氮合酶1在支气管哮喘发病机制及遗传中的作用 源于最近描述的NOS 1多态性之一 由内含子三核苷酸串联重复序列组成， 重复序列已牵连在发病机制的几个 神经系统疾病包括亨廷顿病的疾病。初步人体研究 本文综述表明，携带NOS 1等位基因的轻度哮喘患者， 更多数量的内含子三核苷酸重复具有更低且更少的可变性 过期NO水平。这种关联已在患有 囊性纤维化这些观察提示了以下假设： NOS 1的多态性与呼出的NO的可变水平相关， 哮喘患者的气道高反应性;这些等位基因变异 在NOS 1中，结果变量NO产生表现为显著不同 具有可变临床特征的哮喘表型代表重要线索 哮喘的遗传多样性。为了验证这一假设，我们提出了三个 具体目标。在第一个具体目标中，我们将确定 NOS 1基因座基因型、基线肺功能和混合呼气相之间 NO在轻中度哮喘患者队列中的作用。如果我们假设 正确，我们希望证明携带等位基因变异的哮喘患者 重复次数越多，呼出气中排出的NO越少， 对非特异性支气管激发操作反应相对较低， 与具有相似临床特征的哮喘患者相比， 更少的重复。在接下来的两个具体目标中，我们将研究 一组具有不同NOS 1多态性的哮喘受试者的应答 具体的临床干预措施，包括过敏原支气管激发 吸入、缓激肽激发、高渗盐水激发和戒断 吸入性皮质类固醇我们希望能证明， 不同的NOS 1等位基因将对这些不同的 挑战我们希望，完成这些具体目标将有助于我们 了解一氧化氮作为哮喘介质和指标的作用 气道炎症，遗传差异如何影响这些作用，以及如何 神经机制可能有助于病理生理学和神经病学， 哮喘

项目成果

Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.

• DOI: 10.1016/s0140-6736(09)61492-6
• 发表时间: 2009-11-21
• 期刊: LANCET
• 影响因子: 168.9
• 作者: Wechsler, Michael E.;Kunselmon, Susan J.;Chinchilli, Vernon M.;Bleecker, Eugene;Boushey, Homer A.;Calhoun, William J.;Ameredes, Bill T.;Castro, Mario;Craig, Timothy J.;Denlinger, Loren;Fahy, John V.;Jarjour, Nizar;Kazani, Shamsah;Kim, Sophia;Kraft, Monica;Lazarus, Stephen C.;Lemanske, Robert F., Jr.;Markezich, Amy;Martin, Richard J.;Permaul, Perdita;Peters, Stephen P.;Ramsdell, Joe;Sorkness, Christine A.;Sutherland, E. Rand;Szefler, Stanley J.;Walter, Michael J.;Wasserman, Stephen I.;Israel, Elliot
• 通讯作者: Israel, Elliot