Association between ANP and NPRA Gene Polymorphisms and Severity of Atopy and Ast

ANP 和 NPRA 基因多态性与特应性和 Ast 严重程度之间的关联

• 批准号: 7472723
• 负责人: Shyam S Mohapatra
• 金额: $ 19.94万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472723
• 关键词: 1p36; Adult; African American; Age; Allergic; American Lung Association; Animal Model; Asthma; Atrial Natriuretic Factor; Biological Markers; Bronchial Hyperreactivity; C-terminal; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Caucasoid Race; Child; Childhood; Chromosomes; Chronic; Chronic Obstructive Airway Disease; Chronic Obstructive Asthma; Class; Clinical Research; Clinical Trials; Complex; Country; DNA; Dendritic Cells; Development; Disease; Disease susceptibility; Drug Delivery Systems; Embryo; Epithelial; Ethnic Origin; Gender; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Haplotypes; Heart Atrium; Hospitalization; Human; Hypersensitivity; IgE; Immunology procedure; Incidence; Individual; Inflammation; Inflammatory; Interferon Type II; Knowledge; Lead; Letters; Lung; Lung diseases; Measures; Mediator of activation protein; Mus; N-propionylprocainamide; Natriuretic Peptides; Neonatal; Numbers; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Plasma; Play; Polymorphism Analysis; Population; Population Control; Predisposition; Public Health; Rate; Receptor Gene; Research Personnel; Role; Sampling; Serum; Severities; Severity of illness; Subgroup; Symptoms; Testing; Therapeutic; Thinking; Thymocyte Development; Thymus Gland; Time; atopy; base; cohort; disorder risk; genetic variant; health care service utilization; human disease; mast cell; mortality; novel; peptide I; polypeptide C; receptor; response; young adult

DESCRIPTION (provided by applicant): This proposal aims to investigate the atrial natriuretic peptide (ANP) and its receptor, NPRA, as candidate genes for asthma, a common chronic inflammatory lung disease to which about 4000 individuals succumb each year in this country. The complexity of asthma is reflected in the large number of genetic factors that can make up a specific asthma phenotype. The genes contributing to asthma are thought to be susceptibility loci that influence, but do not determine, the overall disease risk. It is plausible that genes that determine the overall disease risk are yet to be identified. ANP, the C-terminal peptide of pro-ANP, plays a pivotal role in the development of thymocytes in embryonic and neonatal mice and promotes a T helper type 2 (Th2)-dominant response in the lungs of adult mice and therefore may contribute to the genesis and progression of asthma. NPRA deficient mice are protected from asthma. The ANP-NPRA pathway is involved in directing human DCs to promote Th2-dominance and human mast cells to release mediators in both an IgE-dependent and - independent manner. A preliminary association analysis of 4 SNPs of NPPA gene were typed in 488 patients with well-characterized asthma (cases) and in 186 healthy controls without asthma shows that there is a significant associations for asthma between a common haplotype (CGTG) in both African Americans and Caucasians. These findings have led to the hypothesis that NPPA and NPR1 are important susceptibility loci for asthma and that there are specific polymorphisms associated with different atopy (e.g., total serum IgE) and asthma (e.g., bronchial hyperreactivity) phenotypes. The primary goal of this submission is to determine if polymorphisms in the gene for ANP, NPPA, and the NPRA receptor gene, NPR1, are associated with asthma. We hypothesize that NPPA and NPR1 are important susceptibility loci for asthma and that there are specific polymorphisms associated with different atopy (e.g. total serum IgE) and asthma (e.g., bronchial hyperreactivity) phenotypes. To test this hypothesis, the following specific aims are proposed. In Aim #1, it is planned to determine the association between genotype and haplotype SNPs (htSNP) in ANP (NPPA) and NPRA (NPR1) genes in asthmatics and matched healthy controls in a population of African-Americans and Caucasians. The associations among haplotypes in 714 subjects with asthma and 500 controls matched for age, ethnicity, BMI and gender will be examined using DNA collected from several clinical trials from the American Lung Association, Asthma Clinical Research Centers (ALA-ACRC). Additionally, the htSNP approach will be used to capture genetic variability in association analyses. In Aim #2, it is proposed to investigate whether pro-ANP (I-98) can be biomarker of asthma and/or atopy. It is planned to use serum samples from a subgroup of well-characterized allergic/asthmatic subjects (n = 714 cases and 500 controls), collected through ALA-ACRC asthma studies. Thus, serum levels of pro-ANP will be measured by an established EIA and correlated with genotype and haplotype SNPs studied in aim#1 with disease severity of these patients and with total IgE estimated in the same serum samples. These results will indicate whether ANP can be biomarker for asthma. The analysis of polymorphism in this novel candidate gene for asthma is expected to increase our knowledge of NPPA and NPR1 genes which play a critical role in several common human diseases including asthma. PUBLIC HEALTH RELEVANCE: The incidence of asthma and the rates of hospitalization, health care utilization and mortality because of asthma are increasing worldwide. Although better management has decreased asthma mortality in this country, about 4000 individuals will die each year from asthma. Asthma is the most common disease of childhood. African American children and young adults are three to four times more likely than whites to be hospitalized for asthma and four to six times more likely to die from asthma. Asthma is a complex disease and this complexity is reflected in the large number of genetic factors that can make up a specific asthma phenotype. This proposal aims to investigate the association of polymorphism of a positional candidate gene, ANP and its receptor, which appear to play a critical role in pathogenesis of many inflammatory lung diseases including asthma and chronic obstructive pulmonary diseases. The existing results indicate that inhibiting this pathway might be therapeutic for asthmatics. Establishing an association of ANP polymorphisms will not only confirm the importance of this gene in asthma, but may also indicate who will benefit from an ANP-based therapy.

描述（由申请人提供）：本提案旨在研究心房钠尿肽（ANP）及其受体 NPRA 作为哮喘的候选基因，哮喘是一种常见的慢性炎症性肺病，我国每年约有 4000 人死于该病。哮喘的复杂性体现在可以构成特定哮喘表型的大量遗传因素上。导致哮喘的基因被认为是影响但不决定总体疾病风险的易感位点。决定总体疾病风险的基因尚未确定，这似乎是合理的。 ANP 是 ANP 前体的 C 端肽，在胚胎和新生小鼠的胸腺细胞发育中发挥着关键作用，并促进成年小鼠肺部的 T 辅助细胞 2 型 (Th2) 主导反应，因此可能有助于哮喘的发生和发展。 NPRA 缺陷小鼠可免受哮喘侵害。 ANP-NPRA 通路参与指导人类 DC 促进 Th2 优势，并指导人类肥大细胞以 IgE 依赖性和非依赖性方式释放介质。对 488 名患有明确哮喘的患者（病例）和 186 名无哮喘的健康对照者进行的 NPPA 基因 4 个 SNP 的初步关联分析表明，两个非裔美国人的共同单倍型 (CGTG) 与哮喘之间存在显着关联和白人。这些发现导致了这样的假设：NPPA 和 NPR1 是哮喘的重要易感位点，并且存在与不同特应性（例如血清总 IgE）和哮喘（例如支气管高反应性）表型相关的特定多态性。本次提交的主要目标是确定 ANP、NPPA 和 NPRA 受体基因 NPR1 基因的多态性是否与哮喘相关。我们假设 NPPA 和 NPR1 是哮喘的重要易感位点，并且存在与不同特应性（例如血清总 IgE）和哮喘（例如支气管高反应性）表型相关的特定多态性。为了检验这一假设，提出了以下具体目标。在目标 1 中，计划确定非裔美国人和白种人群体中哮喘患者和匹配的健康对照中 ANP (NPPA) 和 NPRA (NPR1) 基因的基因型和单倍型 SNP (htSNP) 之间的关联。将使用从美国肺脏协会哮喘临床研究中心 (ALA-ACRC) 的多项临床试验中收集的 DNA 来检查 714 名哮喘受试者和 500 名年龄、种族、BMI 和性别匹配的对照者的单倍型之间的关联。此外，htSNP 方法将用于捕获关联分析中的遗传变异性。在目标 2 中，建议研究 ANP 前体 (I-98) 是否可以作为哮喘和/或特应性的生物标志物。计划使用通过 ALA-ACRC 哮喘研究收集的一组明确的过敏/哮喘受试者（n = 714 例病例和 500 名对照）的血清样本。因此，pro-ANP 的血清水平将通过已建立的 EIA 进行测量，并将其与目标#1 中研究的基因型和单倍型 SNP 以及这些患者的疾病严重程度以及相同血清样本中估计的总 IgE 相关联。这些结果将表明 ANP 是否可以作为哮喘的生物标志物。对这个新的哮喘候选基因的多态性分析有望增加我们对 NPPA 和 NPR1 基因的了解，这些基因在包括哮喘在内的几种常见人类疾病中发挥着关键作用。 公共卫生相关性：全球范围内哮喘的发病率以及因哮喘而住院的比率、医疗保健的利用率和死亡率都在增加。尽管更好的管理降低了该国的哮喘死亡率，但每年仍有约 4000 人死于哮喘。哮喘是儿童期最常见的疾病。非裔美国儿童和年轻人因哮喘住院的可能性是白人的三到四倍，死于哮喘的可能性是白人的四到六倍。哮喘是一种复杂的疾病，这种复杂性反映在可以构成特定哮喘表型的大量遗传因素上。该提案旨在研究位置候选基因 ANP 及其受体多态性的关联，该基因似乎在许多炎症性肺病（包括哮喘和慢性阻塞性肺病）的发病机制中发挥着关键作用。现有的结果表明，抑制该途径可能对哮喘患者有治疗作用。建立 ANP 多态性的关联不仅可以证实该基因在哮喘中的重要性，还可以表明谁将从基于 ANP 的治疗中受益。