Maternal Genetic Variation and Risk of Adverse Pregnancy Outcomes

描述（由申请人提供）：早产，小胎龄（SGA）和妊娠高血压（PIH）是影响母亲和孩子健康的主要妊娠并发症，通常导致分娩后进入新生儿重症监护病房。我们提出了一种高效、密集的基于通路的遗传变异与早产、SGA和PIH的分析，以实现以下具体目标：(1)研究细胞周期和凋亡通路多态性与早产、SGA、足月SGA和妊娠高血压（PIH）风险之间的关系；(2)探讨血管生成通路基因多态性与SGA、PIH风险的关系；(3)探讨炎症通路基因多态性与早产风险、总SGA和足月SGA、PIH的关系。为了实现这些目标，我们将借鉴一项具有良好特征的早产前瞻性队列研究，即妊娠、感染和营养研究（PIN），该研究在大约10年的时间里招募了5000多名妇女。在一个嵌套的病例对照子集中，包括早产儿（n=379）、足月SGA （n=281，另外90例为早产儿）和PIH病例（n=468），以及一组随机对照（n= 936），已经提取了DNA并可用于遗传分析。我们建议使用基于单倍型的方法对Illumina 1536芯片上大约93个感兴趣的基因进行DNA样本分析。我们已经确定的优先途径与胎盘期有关，这是一个发育时期，这些结果可能与病因有关。通过额外的投资，该队列可以提供迄今为止最全面的证据，将这些感兴趣的途径中的变异与这些不良出生结局联系起来。公共卫生相关性：本研究有望显著提高对早产、SGA和PIH遗传流行病学的理解。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): Preterm birth, small-for-gestational age (SGA) and pregnancy induced hypertension (PIH) are major pregnancy complications that impact the health of the mother and the child, often resulting in admission to the neonatal intensive care unit following delivery. We propose a highly efficient, intensive pathway-based analysis of genetic variation and preterm delivery, SGA, and PIH that addresses the following specific aims: (1) To investigate the relationship between polymorphisms in the cell-cycle and apoptosis pathways with risk of preterm delivery, SGA, term SGA and pregnancy induced hypertension (PIH); (2) To investigate the relationship between polymorphisms in the angiogenesis pathway with risk of SGA and PIH; (3) To investigate the relationship between polymorphisms in the inflammation pathway with risk of preterm delivery, total and term SGA, and PIH. To address these aims we will be drawing on a well- characterized prospective cohort study of preterm delivery, the Pregnancy, Infection and Nutrition study (PIN), which enrolled over five thousand women over the course of approximately 10 years. In a nested case-control subset of preterm (n=379), term SGA (n=281, an additional 90 are preterm), and PIH cases (n=468) and a random group of controls (n = 936), DNA has already be extracted and is available for genetic analyses. We propose to analyze these DNA specimens using a haplotype-based approach for approximately 93 genes of interest on the Illumina 1536 chip. The priority pathways we have identified bear relevance to the period of placentation, which is a period of development at which these outcomes may be etiologically linked. With additional investment, this cohort could provide the most comprehensive evidence to date linking variants in these pathways of interest with these adverse birth outcomes. PUBLIC HEALTH RELEVANCE: This study promises to generate a markedly enhanced understanding of the genetic epidemiology of preterm, SGA and PIH. This information will provide a foundation for studying other adverse pregnancy outcomes with shared biological mechanisms.