Genome-wide association studies of prematurity and its complications

描述（由申请人提供）：早产导致早产儿的分娩是一个复杂的问题，对个人，家庭和社会产生巨大影响。今年美国将有50万儿童早产，全世界将有500万儿童死于早产及其并发症。它是残疾调整生命年（DADs）的最大贡献者，DADs是衡量疾病终身影响的指标。尽管这一问题很重要，而且在贫穷和少数民族人口中的发生率不成比例，但没有足够的资源来发现其根本病因。早产的最大单一原因是自发性早产，怀疑的触发因素包括感染，压力，营养不良和遗传因素。大量的家庭和双胞胎研究提供了强有力的证据，表明遗传因素构成了约40%的早产风险。早产的唯一最佳预测因素是以前的早产。研究早产遗传因素的一个主要挑战是风险可能存在于母亲和她的子宫或婴儿/胎盘中。因此，任何研究早产的方法都应该考虑婴儿和母亲的风险，环境协变量和相互作用。丹麦国家出生队列研究是一项成熟的前瞻性队列研究，其优点是在妊娠早期招募结果尚不清楚的妇女，从而最大限度地减少数据收集和抽样的偏倚。丹麦的这项研究从怀孕的头三个月开始跟踪了96，000多名妇女，并获得了有关母亲和儿童结局的广泛生物学和流行病学数据。在这项提案中，我们将使用1,000例非常明确的自发性早产病例进行全基因组病例/对照分析，其中母亲和婴儿的生物样本来自丹麦国家出生队列研究。这些将与1，000名在妊娠39或40周出生的母亲/婴儿对照相匹配。广泛的流行病学变量将用作分析中的协变量。为了复制积极的发现，我们可以访问来自同一个丹麦国家出生队列研究的额外对照的深层资源，以及来自美国大样本收集的1,000多个母亲/父亲/早产儿三联体，以及另外1,000个美国病例/对照，这些病例/对照针对非洲裔美国人进行了富集，这是一个已知早产率很高的人群。涉及环境因素的阳性结果可以进一步研究，因为丹麦队列有妊娠早期和中期的母体血清样本，以及额外的流行病学和结局数据。这项研究应该能够更好地了解分娩的生物学，确定在早产中发挥作用的常见遗传因素，并提出可以延长妊娠的环境修改，目的是改善新生儿和成人的结果。

DESCRIPTION (provided by applicant): Preterm labor resulting in the delivery of a premature infant is a complex problem with an enormous impact on individuals, families and society. 500,000 children will be born prematurely in the U.S. this year, and worldwide 5 million will die of prematurity and its complications. It is the single largest contributor to DALYs, disability adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, insufficient resources have been targeted to discover its underlying etiology. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Numerous family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. The single best predictor for preterm delivery is a previous preterm birth. A major challenge in studying genetic factors in prematurity is that the risk could reside either in the mother and her uterus or in the infant/placenta. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort Study is a well established, prospective cohort study that has the advantage of enrolling women early in pregnancy when the outcome is still unknown, so that bias in data collection and sampling is minimized. The Danish study has followed over 96,000 women beginning in the first trimester of pregnancy and has extensive biological and epidemiologic data on the outcomes of both mother and child. In this proposal, we will do a genome-wide case/control analysis using 1,000 very well characterized cases of spontaneous preterm birth, with biological samples on the mother and infant, drawn from the Danish National Birth Cohort Study. These will be matched to 1,000 mother/infant controls, born at 39 or 40 weeks gestation. Extensive epidemiologic variables will be used as covariates in the analysis. To replicate positive findings, we can access the deep resource of additional controls from the same Danish National Birth Cohort Study as well as more than 1,000 mother/father/preterm infant triads available from a large sample collection in the United States, and a further 1,000 U.S. case/controls enriched for African-Americans, a population known to have high rates of preterm labor. Positive results involving environmental factors can be further investigated, as the Danish cohort has maternal serum samples from early and mid pregnancy, as well as additional epidemiologic and outcome data. The study should enable a better understanding of the biology of parturition, identify common genetic factors that play a role in prematurity and suggest environmental modifications that can prolong gestations, with the goal of improving both neonatal and adult outcomes.