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Fetal Genetic Contributions to Preeclampsia

胎儿遗传对先兆子痫的影响

基本信息

批准号：
8445231
负责人：
Andrew DeWan
金额：
$ 11.87万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445231
关键词：
Address Affect Area Bioinformatics Biological Biological databases Biology Candidate Disease Gene Case-Control Studies Clinical Medicine Conceptions DNA Data Databases Development Disease Early identification Excision Fetus Functional disorder Genes Genetic Genetic Predisposition to Disease Genotype Goals Health Heritability Hybrids Hyperglycemia Individual Informatics Joints Knowledge Life Literature Logistic Regressions Methodology Methods Modeling Mothers Outcome Study Participant Pathogenesis Pathway Analysis Pathway interactions Pharmacological Treatment Phase Phenotype Placenta Play Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Process Proteins Publishing Research Research Personnel Risk Role Sampling Scheme Syndrome Variant Weight base case control clinical practice data mining database of Genotypes and Phenotypes fetal genetic epidemiology genetic variant genome wide association study genome-wide infant morbidity/mortality novel offspring

项目摘要

DESCRIPTION (provided by applicant): Preeclampsia is a life-threatening complication of pregnancy affecting maternal and fetal health of millions worldwide. Consequences of preeclampsia include both short- and long-term adverse health effects for both the mother and her baby. Despite decades of research providing evidence of a strong heritability component, specific genetic contributions have yet to be identified. A critical barrier to our understanding o the genetics of preeclampsia has been a nearly exclusive focus on maternal genetic contributions. The fetus is now known to be an active participant in pregnancy, and the central role of the placenta in the pathogenesis of preeclampsia implies that the fetus is likely to play a pivotal role in the disease process. The broad long-term goal of this research is to advance substantially our current and limited understanding of the genetic etiology of preeclampsia. Utilizing existing DNA from a previous case-control study of preeclampsia, together with genotyping data available in dbGAP on mother-baby pairs who have been similarly characterized on case and control status, we propose to build upon a preliminary genome-wide study of maternal genetic contributions to preeclampsia; this will be among the first studies to specifically examine fetal genetic contributions to preeclampsia and explore joint maternal-fetal gene effects. Utilizing contemporary, methodologically rigorous approaches, we will address the following specific aims: Aim 1: Develop a Pathway Analysis database for preeclampsia incorporating genetic information from published literature, expression databases, and biological pathways to identify an informative set of candidate fetal SNPs or CNVs for association studies of preeclampsia; Aim 2: To identify distinct fetal genetic variants associated with the maternal syndrome of preeclampsia. As a secondary aim, we propose to explore methodologies for identifying joint maternal-fetal genetic effects. The proposed research will develop and advance our understanding of the genetics of preeclampsia by studying the fetal contributions to preeclampsia using a combined genome-wide and candidate gene approach. In addition, we will explore individual and joint contributions of both maternal and fetal genotypes. Identifying distinct fetal genetic contributions to preeclampsia will inform biological understanding of the disease process, and could have a major impact on clinical practice by enabling early identification of at-risk pregnancies defined by fetal and maternal genetics. The data from this R21 will provide pilot data to inform development of an R01 to extend the findings of this study and to target and confirm the biological basis for genetic variants through placental expression studies and re-sequencing of relevant genes. The proposed research has tremendous potential to impact knowledge and practice in this area with its pioneering emphasis on fetal genetics and a carefully planned, interdisciplinary and integrated phased approach using state-of-the-art methodologies from the fields of statistical genetics, epidemiology, and clinical medicine.

描述(由申请人提供)：先兆子痫是一种危及生命的妊娠并发症，影响全球数百万孕妇和胎儿的健康。先兆子痫的后果包括对母亲和婴儿的短期和长期不利健康影响。尽管几十年的研究提供了很强的遗传性成分的证据，但具体的遗传贡献尚未确定。我们理解先兆子痫遗传学的一个关键障碍是几乎完全专注于母亲的遗传贡献。现在已知胎儿是妊娠的活跃参与者，而胎盘在先兆子痫发病机制中的中心作用意味着胎儿可能扮演着在疾病过程中起着关键作用。这项研究的广泛的长期目标是大幅推进我们目前对先兆子痫遗传病因的有限理解。利用来自先前先兆子痫病例对照研究的现有DNA，以及在DBGaP中对具有类似病例和对照状态特征的母婴对的基因分型数据，我们建议建立在母体遗传对先兆子痫的初步全基因组研究的基础上；这将是第一批专门研究胎儿遗传对先兆子痫的贡献并探索母婴联合基因效应的研究之一。利用当代的、方法严谨的方法，我们将解决以下具体目标：目标1：开发一个用于子痫前期的路径分析数据库，整合已发表文献、表达数据库和生物路径中的遗传信息，以确定用于子痫前期相关性研究的候选胎儿SNPs或CNV的信息组；目标2：识别与母体先兆子痫综合征相关的不同的胎儿基因变异。作为第二个目标，我们建议探索识别母婴联合遗传效应的方法。这项拟议的研究将通过使用全基因组和候选基因相结合的方法来研究胎儿对先兆子痫的贡献，从而发展和推进我们对先兆子痫遗传学的理解。此外，我们还将探讨母体和胎儿的个体和共同贡献。确定不同的胎儿基因对先兆子痫的影响将有助于生物学上对疾病过程的理解，并可能对临床实践产生重大影响，因为能够及早识别由胎儿和母体遗传学定义的高危妊娠。来自R21的数据将为R01的开发提供先导数据，以扩大这项研究的发现，并通过胎盘表达研究和相关基因的重新测序来靶向和确认遗传变异的生物学基础。这项拟议的研究具有巨大的潜力来影响这一领域的知识和实践，其开创性的重点是胎儿遗传学，并使用统计遗传学、流行病学和临床医学领域的最新方法，采用精心规划的、跨学科的和综合的分阶段方法。