Establishing Precursors of Food Allergy in Newborns

描述(由申请人提供)：食物过敏(FA)是一种由免疫球蛋白(Ig)E介导的食物超敏反应引起的疾病，在美国是一个日益严重的临床和公共卫生问题。大多数儿童FA发生在生命的头几年，但缺乏一项前瞻性出生队列研究，专门设计在大量美国人口中确定FA的产前前体。虽然阳性家族史是公认的过敏性疾病的预测因子，但调节个体对FA易感性的特定遗传标记在很大程度上仍未被探索。这项应用的中心焦点是利用波士顿出生队列的广泛资源，调查与FA发展有关的产前和遗传因素。这个队列由大约6000名新生儿和他们的母亲组成，他们在波士顿医疗中心注册或正在注册。在最初招募时收集的信息包括产前流行病学和临床变量、出生结果以及母亲和脐带血样本。这一队列从出生起就被前瞻性地跟踪，以确定FA和其他过敏性疾病的事件病例。在出生后的随访中收集的信息包括FA问卷；总的和食物和航空过敏原特定的IgE；包括ICD医生诊断代码的医疗记录；以及儿童的静脉血样。为了最大限度地提高成本效益，将使用嵌套病例对照设计，包括从波士顿出生队列中确定的总共400个FA事件病例和800个无症状和非敏感型对照。本研究的主要目的是：(1)评估产前因素与出生后头两年FA发生的关系；(2)评估候选基因多态与出生后头两年FA发生的关系。这项研究将根据目前的文献，集中在涉及FA重要免疫通路的有希望但未经证实的候选基因，包括抗原提呈；IgE受体；天然免疫；TH1倾斜；TH2倾斜；TH17倾斜；T调节；炎症；趋化因子等。这项研究具有以下优势：(1)通过使用大的、现有的出生队列和嵌套的病例对照设计，具有高成本效益；(2)能够建立时间关系，并为因果关系提供强有力的证据；(3)能够全面检查FA的产前和遗传前体；(4)大样本量，确保有足够的能力检测因果关系；(5)创新的基因环境方法，并利用最先进的高通量基因分型技术和统计方法；(6)高度互动和经验丰富的研究团队，在这一出生队列和其他人群中进行分子和遗传研究的成功记录，以及(7)鉴于良好的基础设施和资源，未来对FA的研究具有巨大的潜力。这项研究将有助于开发一种新的、有前景的范例来识别在儿童早期发展FA的高风险新生儿，这可能导致在以后的生活中预防或减轻FA的干预措施。在美国，食物过敏正在成为一个主要的临床和公共卫生问题；也是最常见的过敏反应急诊室就诊的原因，这可能是致命的。大多数FA病例发生在生命的最初几年；但关于产前和遗传因素对FA发展的影响的数据很少，这将是本研究的重点。

DESCRIPTION (provided by applicant): Food allergy (FA), a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. Most childhood FA develops in the first few years of life, but there is a lack of a prospective birth cohort study that is specifically designed to identify prenatal precursors of FA in a large U.S. population. While a positive family history is a well-recognized predictor of allergic diseases, specific genetic markers that can modulate individual susceptibility to FA remain largely unexplored. The central focus of this application is to investigate prenatal and genetic factors in relation to the development of FA, using the extensive resources of Boston Birth Cohort. This cohort consists of ~6,000 newborns and their mothers enrolled or being enrolled at the Boston Medical Center. The information collected at the initial recruitment included prenatal epidemiological and clinical variables, birth outcomes, and maternal and cord blood samples. This cohort has been prospectively followed from birth onward to identify incident cases of FA and other allergic diseases. The information collected at postnatal follow-ups includes FA questionnaires; total and food- and aero-allergen-specific IgE; medical records including ICD codes of physician diagnosis; and child's venous blood sample. To maximize cost-efficiency, a nested case-control design will be used, including a total of 400 FA incident cases and 800 non-symptomatic and non-sensitized controls identified from the Boston Birth Cohort. This study's primary aims are: (1) To assess the association of prenatal factors with development of FA in the first two years of life; and (2) To assess the association of candidate gene polymorphisms with development of FA in the first two years of life. This study will focus on promising yet unproven candidate genes involved in the important immune pathways of FA based on current literature, including Antigen presentation; IgE receptor; Innate immunity; TH1 skewing; TH2 skewing; TH17 skewing; T-Regulatory; Inflammatory; Chemokines; and Others. This study has following strengths:(1) highly cost-efficient by using a large, existing birth cohort and a nested case-control design; (2) a prospective data collection that can establish temporal relationships, and provide strong evidence for cause-and-effect; (3) a capability of examining a comprehensive array of prenatal and genetic precursors of FA; (4) a large sample size that assures adequate power to detect causal relations; (5) an innovative gene-environment approach and utilization of the state-of-the-art high-throughput genotyping technology and statistical methods; (6) a highly interactive and experienced research team with a successful track record in conducting molecular and genetic research in this birth cohort and in other populations, and (7) a tremendous potential for future studies of FA, given the well-established infrastructure and resources. This study will help develop a novel and promising paradigm to identify newborns at high risk of developing FA in early childhood, which may lead to interventions that prevent or mitigate FA later in life. Food allergy is emerging as a major clinical and public health problem in the US; and is the most common cause of emergency room visits for anaphylaxis which could be fatal. Most cases of FA developed in the first few years of life; but there is a sparse data on prenatal and genetic influence on the development of FA, which will be the focus of this study.