Role of Prenatal Factors and Gene-Environment Interactions in Recurrent Wheezing

描述(由申请人提供)：这一职业发展奖将促进库马尔博士在混合少数民族人群中哮喘和喘息的遗传流行病学领域发展成为一名独立的研究员。培训将在独特的丰富环境中进行，由王晓斌博士、罗伯特·施莱默博士和卡罗尔·奥贝尔博士指导。外部顾问包括詹姆斯·格恩博士和埃斯特万·伯查德博士。培训将包括：遗传流行病学的教学教育；在候选基因和SNP选择、基因分型、遗传数据获取和分析方面的实践经验；了解GxE研究的理论和统计方法；以及发展市中心纵向队列研究的专业知识。这些教育目标将与该项目的具体目标并行实现，具体如下：目标1：我们将评估早产儿和绒毛膜羊膜炎与波士顿出生队列中早期喘息发展的相关性。目的2：我们将开展一项嵌套式病例对照研究，以评估在调整重要协变量、多重比较和群体分层后，目标1中观察到的关联是否可以被候选基因的单个变异进一步改变。我们将对以下几组候选基因的常见基因多态性进行基因分型：1.参与绒毛膜羊膜炎反应途径的基因，包括炎症反应途径和肺损伤途径的重塑/调节。2.免疫调节先天免疫候选基因。该项目的长期科学目标是评估产前因素在多大程度上与儿童早期反复喘息的差异有关，以及这些相关性是否会因遗传变异而改变。这一被调查的地区具有公共卫生意义，因为非裔美国人市中心人口的喘息率和哮喘发生率要高得多，而传统的危险因素无法解释这些差异。然而，早产儿和特别是绒毛膜羊膜炎沿着这些相同的线有不同的分布，这两种共病流行之间的联系有一定的生物学基础。阐明这些关系可能有助于更好地了解差异和预防喘息发病率。(摘要结束)

DESCRIPTION (provided by applicant): This career development award will foster Dr. Kumar's development into an independent investigator in the area of genetic epidemiology of asthma and wheezing in admixed minority populations. Training will occur in a uniquely rich environment with mentoring from Dr. Xiaobin Wang, Dr. Robert Schleimer, and Dr. Carole Ober. External advisors include Dr. James Gern and Dr. Esteban Burchard. Training will include: didactic education in genetic epidemiology; practical experience in candidate gene and SNP selection, genotyping, genetic data acquisition and analysis; understanding of theoretical and statistical methods of GxE research; and developing expertise in inner city longitudinal cohort studies. These educational goals will be achieved in parallel to the project's specific aims as follows: Aim 1: We will evaluate the association of prematurity and chorioamnionitis with the subsequent development of early life wheezing in the Boston Birth Cohort. Aim 2: We will carry out a nested case control study to evaluate whether the associations observed in Aim 1 can be further modified by individual variants of candidate genes, after with adjustment for important covariates, multiple comparisons and population stratification. We will genotype common gene polymorphisms of the following groups of candidate genes: 1. Genes which are involved in the pathways of response to chorioamnionitis, including inflammatory response pathways and remodeling/modulation of lung injury pathways. 2. Immunoregulatory Innate Immunity Candidate Genes. The long term scientific goal of the project is to evaluate the extent to which prenatal factors are associated with disparities in recurrent early childhood wheezing, and whether these associations are modified by genetic variation. This under investigated area is of public health significance because African American inner city populations have much higher rates of wheezing and asthma ,and traditional risk factors do not explain these disparities. However, prematurity and specifically chorioamnionitis are differentially distributed along these same lines, and there is some biological rationale for the association of these two co-morbid epidemics. Elucidating these relationships may lead to improved understanding of disparities and prevention of wheezing morbidity. (End of Abstract)