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; 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）：该提案旨在研究心房纳特里蛋白肽（ANP）及其受体NPRA作为哮喘的候选基因，这是一种常见的慢性炎症性肺部疾病，该疾病每年约有4000个人在这个国家昏迷。哮喘的复杂性反映在可以构成特定哮喘表型的大量遗传因素中。促成哮喘的基因被认为是影响但不能确定总体疾病风险的易感基因座。确定总体疾病风险的基因尚未确定是合理的。 ANP是pro-ANP的C末端肽，在胚胎和新生儿小鼠的胸腺细胞发展中起关键作用，并促进成年小鼠肺中的T型辅助器2（Th2）较大的反应，因此可能对哮喘的起源和进展有助于。 NPRA缺乏小鼠免受哮喘的保护。 ANP-NPRA途径参与指导人类DC促进Th2-占主导地位和人类肥大细胞以以IgE依赖性和独立方式释放介体。对488例特征良好的哮喘（病例）患者进行了对4个SNP的NPPA基因的初步结合分析，而在没有哮喘的186例健康对照中，在非洲裔美国人和高达亚萨斯人中，常见的单倍型（CGTG）之间的哮喘存在显着关联。这些发现导致了以下假设：NPPA和NPR1是哮喘的重要敏感性基因座，并且存在与不同特应特应（例如总血清IgE）和哮喘（例如支气管性异常反应性）相关的特定多态性。该提交的主要目的是确定ANP，NPPA和NPRA受体基因NPR1中基因中的多态性是否与哮喘有关。我们假设NPPA和NPR1是哮喘的重要敏感性基因座，并且存在与不同特应特应（例如总血清IgE）和哮喘（例如支气管性高反应性）表型相关的特定多态性。为了检验这一假设，提出了以下特定目标。在AIM＃1中，计划确定ANP（NPPA）和NPRA（NPR1）基因在哮喘患者中的基因型和单倍型SNP（HTSNP）之间的关联，并在非裔美国人和高卢人的人群中匹配健康对照。在714名患有哮喘和500个对照的受试者中，将使用从美国肺肺部临床研究中心（ALA-ACRC）中收集的DNA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AIM＃2中，建议研究Pro-ANP（I-98）是否可以成为哮喘和/或特应特应生物标志物。它计划使用通过ALA-ACRC哮喘研究收集的良好特征过敏/哮喘受试者亚组的血清样品（n = 714例和500例对照）。因此，血清AR-ANP的水平将通过已建立的EIA测量，并与AIM＃1中研究的基因型和单倍型SNP相关，并具有这些患者的疾病严重程度，并且在同一血清样品中估计了总IgE。这些结果将表明ANP是否可以成为哮喘的生物标志物。在这个新颖的候选基因中，对哮喘的多态性分析将增加我们对NPPA和NPR1基因的了解，在包括哮喘在内的几种常见人类疾病中起着至关重要的作用。 公共卫生相关性：哮喘的发病率以及由于哮喘而导致的住院，医疗保健利用率和死亡率的发生率正在增加。尽管更好的管理降低了这个国家的哮喘死亡率，但每年大约有4000个人死于哮喘。哮喘是最常见的儿童疾病。非洲裔美国儿童和年轻人的可能性是白人住院的三到四倍，死于哮喘的可能性是四到六倍。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。该提案旨在研究位置候选基因，ANP及其受体的多态性的关联，它们在许多炎症性肺部疾病（包括哮喘和慢性阻塞性肺部疾病）的发病机理中似乎起着关键作用。现有的结果表明，抑制这种途径可能对哮喘患者具有治疗性。建立ANP多态性的关联不仅可以确认该基因在哮喘中的重要性，而且还可能表明谁将从基于ANP的治疗中受益。