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：（改编自申请人的描述）调查人员 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来评估 处方药和非处方药在病因学中的遗传介导作用 人类先天缺陷。特别关注的是增加的风险 常见的出生缺陷，新生儿持续性肺动脉高压（PPHN）， 妊娠晚期接触非甾体抗炎药后 （NSAIDs），特别是布洛芬，一种最常见的药物 怀孕期间使用过的药剂。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，以检验这种增加的假设 风险与参与代谢的遗传介导因素有关 非甾体抗炎药。 在目标 2 中，他们建议使用复杂的技术方法来识别 CYP2D6、CYP3A4 和 CYP3A7 以及其他基因启动子中的突变 改变这些基因的发育和组织特异性表达 胎儿和新生儿。一旦鉴定出多态性，研究人员将 通过应用系统地评估它们在人类中可能的病因作用 这些新工具可用于 SEU-BDS 和 SEU-BDS 收集的当前和未来数据 CDC-NBDPS，两项大型且独特的流行病学出生缺陷研究 收集遗传物质和产前药物的详细信息 曝光。