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

描述（由申请人提供）：先兆子痫的病因尚不清楚，但假设是由异常胎盘形成引起的。胎盘形成异常是最常见的妊娠并发症之一，在美国健康的初产妇女中发病率在2%至7%之间，胎盘形成异常对孕产妇和胎儿的发病率和死亡率有很大的风险。虽然母亲吸烟增加了几个主要的妊娠并发症的风险，但它却使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了未开发的线索。我们建议利用挪威母亲和儿童队列研究，这是一个目前登记了超过86，000例妊娠的大型基于人群的出生队列，以解决与先兆子痫风险相关的以下具体目标：1）检查细胞凋亡，吸烟解毒，血管生成和炎症途径中的母体和胎儿遗传变异; 2）检查主动和被动吸烟暴露以及上述基因变异的联合效应; 3）检查多个风险等位基因的联合效应。我们将选择1500例经验证的单胎先兆子痫病例，从这些病例中采集母体和脐带血，并将其与随机选择的具有可用生物标本的对照组进行匹配。将使用Illumina Goldengate 1536定制芯片提取母体和胎儿DNA并进行基因分型，这将使我们能够测量大约93个基因的全基因变异。此外，将纳入祖先信息标记物，以控制潜在的人群分层。我们将在病例中对母亲吸烟进行过度抽样，以使吸烟率约等于对照组的11%，这将为我们提供检测基因-环境相互作用的极好能力，即使是相对罕见的等位基因。鉴于大规模的遗传学研究先兆子痫以前没有被报道;我们提出的候选基因途径是新的和生物学上合理的;和胎儿的遗传变异以前没有被评估与先兆子痫，尽管事实上，胎盘是胎儿的遗传起源，这个项目将提供重要的新信息先兆子痫的病因学。公共卫生相关性：这项研究有望产生一个显着增强的了解先兆子痫的遗传流行病学考虑到我们的研究规模大，检测主要和相互作用的影响，能力，考虑母亲和胎儿的基因，遗传评估的广度和深度，并提供母亲报告的吸烟状态在怀孕期间，一个公认的原因，降低先兆子痫的风险。这些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.