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利钠肽（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，在美国每年约有4000人死于哮喘。哮喘的复杂性反映在大量的遗传因素中，这些遗传因素可以构成特定的哮喘表型。导致哮喘的基因被认为是影响但不决定整体疾病风险的易感基因座。这是合理的，基因决定的整体疾病风险尚未确定。心钠素（pro-ANP）的C-末端肽在胚胎和新生小鼠胸腺细胞的发育中起关键作用，并促进成年小鼠肺中的辅助性T细胞2型（Th 2）-显性应答，因此可能有助于哮喘的发生和进展。NPRA缺陷型小鼠可免受哮喘。ANP-NPRA通路参与指导人DC促进Th 2优势和人肥大细胞以IgE依赖性和非依赖性方式释放介质。对488例哮喘患者和186例非哮喘健康对照者的NPPA基因4个SNPs进行了初步关联分析，结果表明，在非裔美国人和白人中，一个共同的单倍型（CGTG）与哮喘有显著关联。这些发现导致了这样的假设，即NPPA和NPR 1是哮喘的重要易感基因座，并且存在与不同特应性相关的特定多态性（例如，总血清IgE）和哮喘（例如，支气管高反应性）表型。本申请的主要目的是确定ANP、NPPA和NPRA受体基因NPR 1的多态性是否与哮喘相关。我们假设NPPA和NPR 1是哮喘的重要易感基因座，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。为了检验这一假设，提出了以下具体目标。在目标#1中，计划确定在非裔美国人和高加索人的人群中哮喘患者和匹配的健康对照中ANP（NPPA）和NPRA（NPR 1）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）的几项临床试验中收集的DNA，对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进行检查。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，提出研究pro-ANP（I-98）是否可以是哮喘和/或特应性的生物标志物。计划使用通过ALA-ACRC哮喘研究收集的一个充分表征的过敏/哮喘受试者亚组（n = 714例病例和500例对照）的血清样本。因此，将通过已建立的EIA测量pro-ANP的血清水平，并将其与aim#1中研究的基因型和单倍型SNP、这些患者的疾病严重程度和相同血清样品中估计的总IgE相关联。这些结果将提示ANP是否可以作为哮喘的生物标志物。对这一新的哮喘候选基因的多态性分析有望增加我们对NPPA和NPR 1基因的了解，这两个基因在包括哮喘在内的几种常见人类疾病中起着关键作用。 公共卫生相关性：全球范围内哮喘的发病率、住院率、卫生保健利用率和死亡率均呈上升趋势。虽然更好的管理降低了哮喘死亡率在这个国家，大约4000人将死于哮喘每年。哮喘是儿童最常见的疾病。非洲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中。本研究的目的是探讨ANP及其受体基因多态性的相关性，该基因在哮喘和慢性阻塞性肺疾病等多种炎症性肺疾病的发病机制中起着重要作用。现有的结果表明，抑制这一途径可能对哮喘患者有治疗作用。建立心钠素多态性的关联不仅可以证实该基因在哮喘中的重要性，而且还可以表明谁将从基于心钠素的治疗中获益。