Prenatal Smoking, Maternal & Fetal Genetic Variation & Risk of Preeclampsia

描述(申请人提供)：先兆子痫的病因尚不清楚，但推测是由异常胎盘引起的。异常胎盘是最常见的妊娠并发症之一，在美国健康的初产妇女中的发病率在2%至7%之间，胎盘异常对孕产妇和胎儿的发病率和死亡率具有很大风险。尽管母亲吸烟增加了几种主要妊娠并发症的风险，但自相矛盾的是，它将先兆子痫的风险降低了约30%，这可能为这种疾病的病因提供未经开发的线索。我们建议利用挪威母婴队列研究，这是一项基于人群的大型出生队列研究，目前登记了超过86,000名孕妇，以解决以下与先兆子痫风险相关的具体目标：1)检查母婴在细胞凋亡、吸烟解毒、血管生成和炎症途径中的遗传变异；2)检查主动和被动吸烟暴露以及上述基因变异的联合影响；以及3)检查多个高危等位基因的联合影响。我们将选择1500例经过验证的单胎先兆子痫病例，从这些病例中同时采集母体和脐带血，并将它们与随机选择的具有可用生物标本的对照组进行匹配。孕妇和胎儿的DNA将被提取，并使用Illumina Goldengate 1536定制芯片进行基因分型，这将使我们能够测量大约93个基因的全基因变异。此外，血统信息标记将被包括在内，以控制潜在的种群分层。我们将在病例中对母亲吸烟进行过度抽样，以实现吸烟流行率约等于11%的对照，这将为我们提供极好的能力来检测基因与环境的相互作用，即使是相对罕见的等位基因。鉴于先兆子痫的大规模遗传学研究以前没有报道；我们提出的候选基因途径既新颖又生物学上可信；尽管胎盘是胎儿基因起源的事实，但以前还没有评估过与先兆子痫有关的胎儿遗传变异，这个项目将提供与先兆子痫的病因相关的重要新信息。公共卫生相关性：这项研究有望显著提高对先兆子痫的遗传流行病学的了解，因为我们的研究规模很大，检测主要和交互影响的能力很强；同时考虑母体和胎儿基因的能力；遗传评估的广度和深度；以及孕期母亲报告的吸烟状况的可用性，这是降低先兆子痫风险的公认原因。这一信息将为研究具有共同生物学机制的其他不良妊娠结局提供基础。

DESCRIPTION (provided by applicant): The etiology of preeclampsia remains unknown, but is hypothesized to result from abnormal placentation. One of the most common complications of pregnancy, with US incidence rates between 2 per cent and 7 per cent in healthy primiparous women, abnormal placentation carries a substantial risk for maternal and fetal morbidity and mortality. Although maternal smoking increases the risk of several major pregnancy complications, it paradoxically decreases the risk of preeclampsia by an estimated 30 per cent, which may provide unexploited clues into the etiology of this disorder. We propose to utilize the Norwegian Mother and Child Cohort Study, a large population-based birth cohort with over 86,000 pregnancies currently enrolled, to address the following specific aims in relation to risk of preeclampsia: 1) Examine maternal and fetal genetic variation in the apoptosis, smoking detoxification, angiogenesis and inflammation pathways; 2) Examine the joint effects of active and passive smoking exposure and the gene variants described above; and 3) Examine the joint effects of multiple at-risk alleles. We will select 1500 validated, singleton preeclampsia cases from whom both maternal and cord blood was collected and match them to randomly selected controls with available biospecimens. Maternal and fetal DNA will be extracted and genotyped using the Illumina Goldengate 1536 custom chip, which will allow us to measure gene-wide variation in approximately 93 genes. Additionally, ancestry informative markers will be included to control for potential population stratification. We will over-sample maternal smoking among cases to achieve a smoking prevalence approximately equal to controls of 11 per cent, which will provide us excellent power to detect gene-environment interactions, even for relatively rare alleles. Given that large-scale genetic studies of preeclampsia have not previously been reported; that the candidate-gene pathways we propose are both novel and biologically plausible; and that fetal genetic variation has not previously been assessed in relation to preeclampsia despite the fact that the placenta is of fetal genetic origin, this project will provide important new information relevant to the etiology of preeclampsia. PUBLIC HEALTH RELEVANCE: This study promises to generate a markedly enhanced understanding of the genetic epidemiology of preeclampsia given our large study size and excellent power to detect main and interaction effects; the ability to consider both maternal and fetal genes; the breadth and depth of genetic assessment; and the availability of maternally reported smoking status during pregnancy, a well-established cause of reduced risk for preeclampsia. This information will provide a foundation for studying other adverse pregnancy outcomes with shared biological mechanisms.