PHARMACOGENETIC DETERMINANTS OF HUMAN BIRTH DEFECTS

人类出生缺陷的药物遗传学决定因素

• 批准号: 6524772
• 负责人: ALLEN A MITCHELL
• 金额: $ 72.58万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524772
• 关键词: clinical research; congenital cardiovascular disorder; congenital disorders; disease /disorder etiology; embryo /fetus drug adverse effect; gene expression; genetic promoter element; human pregnant subject; human subject; ibuprofen; nonsteroidal antiinflammatory agent; pharmacokinetics; pulmonary hypertension

DESCRIPTION: (Adapted from the Applicant's description) The investigators propose to apply state-of-the-art pharmacogenetic and pharmacoepidemiologic research methods and two large pharmacoepidemiologic databases to assess the genetically-mediated role of prescription and OTC medications in the etiology of human birth defects. A particular focus relates to the increased risk of a common birth defect, persistent pulmonary hypertension (PPHN) of the newborn, following exposure late in pregnancy to nonsteroidal anti-inflammatory drugs (NSAIDs), and particularly ibuprofen, a drug that is among the most commonly used agents in pregnancy. In aim 1, the investigators will apply data from an ongoing epidemiologic study of PPHN to test the hypothesis that this increased risk is related to genetically mediated factors involved in the metabolism of NSATDs. In aim 2, they propose to use sophisticated technologic approaches to identify mutations in the CYP2D6, CYP3A4, and CYP3A7 and other gene promoters that modify developmental and tissue-specific expression of those genes in the fetus and newborn. Once polymorphisms are identified, the investigators will systematically evaluate their possible etiologic roles in humans by applying these new tools to current and future data collected by the SEU-BDS and the CDC-NBDPS, two large and unique epidemiologic birth defect studies that collect both genetic material and detailed information on antenatal drug exposures.

描述：（根据申请人的描述进行了改编）调查人员 建议采用最先进的药物遗传学和药物ePidemiologic 研究方法和两个大型药物电子学数据库评估 处方和OTC药物在病因中的遗传介导的作用 人类的先天缺陷。一个特别的重点与增加的风险有关 常见的先天缺陷，新生儿的持续性肺动脉高压（PPHN）， 在怀孕后期暴露于非甾体类抗炎药 （NSAIDS），尤其是布洛芬，是一种最常见的药物 在怀孕时使用了药物。在AIM 1中，调查人员将应用来自 PPHN正在进行的流行病学研究，以检验以下假设 风险与参与的遗传介导的因素有关 NSATDS。 在AIM 2中，他们建议使用复杂的技术方法来识别 CYP2D6，CYP3A4和CYP3A7和其他基因启动子中的突变 修改这些基因在 胎儿和新生儿。一旦确定了多态性，研究人员将 系统地评估他们在人类中可能的病因学作用 这些新工具是SEU-BDS和 CDC-NBDP，两项大型且独特的流行病学出生缺陷研究， 收集有关产前药物的遗传材料和详细信息 暴露。