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

描述(申请人提供)：这项建议旨在研究心钠素(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部疾病，在美国每年约有4000人死于哮喘。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基因。决定总体疾病风险的基因还没有确定，这似乎是合理的。心钠素是心钠素原的C端肽，在胚胎和新生小鼠胸腺细胞的发育中起关键作用，并促进成年小鼠肺内辅助性T细胞2型(Th2)的显性反应，因此可能参与哮喘的发生和发展。NPRA基因缺陷的小鼠可以免受哮喘的侵袭。ANP-NPRA途径参与引导人树突状细胞促进Th2占优势，人肥大细胞以IgE依赖和非依赖方式释放介质。对488例典型哮喘患者和186例健康对照的NPPA基因4个SNP进行了初步关联分析。结果表明，非裔美国人和高加索人中常见的一种单倍型(CGTG)与哮喘有显著关联。这些发现导致假设NPPA和NPR1是哮喘的重要易感基因，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。这篇论文的主要目的是确定ANP、NPPA和NPRA受体基因NPR1的多态是否与哮喘有关。我们假设NPPA和NPR1是哮喘的重要易感基因，并且存在与不同的特应性(如血清总IgE)和哮喘(如支气管高反应性)表型相关的特异性基因多态。为了验证这一假设，提出了以下具体目标。在目标1中，计划在非裔美国人和高加索人人群中确定ANP(NPPA)和NPRA(NPR1)基因的单倍型SNP(HtSNP)与哮喘患者和匹配的健康对照之间的关联。714名哮喘患者和500名年龄、种族、体重指数和性别匹配的对照组的单倍型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)收集的几项临床试验的DNA来检验。此外，将使用htSNP方法来捕捉关联分析中的遗传变异性。在目标2中，有人提议调查前ANP(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哮喘研究收集的具有良好特征的过敏性/哮喘受试者(n=714例和500名对照)亚组的血清样本。因此，血清心钠素原水平将通过建立的EIA进行测量，并与AIM#1中研究的基因和单倍型SNPs与这些患者的疾病严重程度相关，并与同一血清样本中估计的总IgE相关。这些结果将提示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，这两个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。 与公共卫生的相关性：哮喘的发病率以及因哮喘而住院、卫生保健利用和死亡率在全球范围内都在增加。尽管更好的管理降低了这个国家的哮喘死亡率，但每年仍有约4000人死于哮喘。哮喘是儿童时期最常见的疾病。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上。本研究旨在探讨位置候选基因ANP及其受体的多态性与包括哮喘和慢性阻塞性肺疾病在内的许多炎症性肺部疾病发病机制的关系。现有研究结果表明，抑制这一通路可能对哮喘患者有治疗作用。建立ANP基因多态的关联不仅将证实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。

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.