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

描述（由申请人提供）：子痫前期的病因尚不清楚，但假设是由胎盘异常引起的。异常胎盘是妊娠最常见的并发症之一，在美国健康的初产妇中发病率在2%至7%之间，它对孕产妇和胎儿的发病率和死亡率具有重大风险。虽然孕妇吸烟增加了几种主要妊娠并发症的风险，但它却自相矛盾地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了尚未开发的线索。我们建议利用挪威母婴队列研究（Norwegian Mother and Child Cohort Study），这是一项以人口为基础的大型出生队列研究，目前有超过86,000名孕妇入组，以解决与子痫前期风险相关的以下具体目标：1)检查母亲和胎儿在细胞凋亡、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与上述基因变异的共同影响；3)检验多个高危等位基因的联合效应。我们将选择1500例经过验证的单胎子痫前期病例，这些病例采集了母体和脐带血，并将其与随机选择的具有可用生物标本的对照进行匹配。母体和胎儿的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，将包括祖先信息标记，以控制潜在的群体分层。我们将在病例中对产妇吸烟进行过度抽样，以达到吸烟率约等于11%的对照，这将为我们提供极好的能力来检测基因-环境相互作用，即使是相对罕见的等位基因。鉴于大规模的子痫前期遗传研究以前没有报道；我们提出的候选基因途径既新颖又具有生物学合理性；尽管胎盘是胎儿遗传起源，但胎儿遗传变异与子痫前期的关系尚未得到评估，该项目将为子痫前期的病因学提供重要的新信息。公共卫生相关性：鉴于我们的研究规模大，并且能够很好地检测主要效应和相互作用，本研究有望显著增强对子痫前期遗传流行病学的理解；考虑母体和胎儿基因的能力；遗传评价的广度和深度；孕妇在怀孕期间报告吸烟状况的可用性，这是一个公认的降低子痫前期风险的原因。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.