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: 6382412
• 负责人: ALLEN A MITCHELL
• 金额: $ 70.58万
• 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/6382412
• 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：（根据申请人的描述改编）研究者 建议应用最先进的药物遗传学和药物流行病学 研究方法和两个大型药物流行病学数据库，以评估 处方药和OTC药物在病因学中的遗传介导作用 人类出生缺陷的证据一个特别关注的问题是， 常见的出生缺陷，新生儿持续性肺动脉高压（PPHN）， 在妊娠晚期暴露于非甾体抗炎药后 （非甾体抗炎药），特别是布洛芬，一种最常见的药物， 在怀孕期间使用药物。在目标1中，研究人员将应用来自 正在进行的PPHN流行病学研究，以检验这一假设， 风险与参与代谢的遗传介导因素有关， NSATD。 在目标2中，他们建议使用复杂的技术方法来识别 CYP 2D 6、CYP 3A 4和CYP 3A 7以及其他基因启动子中的突变， 改变这些基因在发育和组织特异性表达， 胎儿和新生儿。一旦确定多态性，研究人员将 系统地评价其可能的病因作用，在人类中， 这些新的工具，以当前和未来的数据收集SEU-BDS和 CDC-NBDPS是两项大型独特的出生缺陷流行病学研究， 收集遗传物质和产前药物的详细信息 暴露。