Genome-wide association studies of prematurity and its complications

描述（由申请人提供）：早产导致的早产是一个复杂的问题，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500万人死于早产及其并发症。它是伤残调整生命年（DALYs）的最大贡献者，伤残调整生命年是衡量疾病终生影响的指标。尽管这一问题很重要，而且在贫困和少数民族人群中发病率很高，但发现其潜在病因的资源不足。早产的最大单一原因是自发性早产，其可疑触发因素包括感染、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，表明遗传因素是导致早产风险的40%。早产的唯一最佳预测指标是以前的早产。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及其子宫或婴儿/胎盘中。因此，任何研究早产的方法都应该考虑到婴儿和母亲的风险、环境协变量和相互作用。丹麦国家出生队列研究是一项建立良好的前瞻性队列研究，其优势是在结果尚不清楚的妊娠早期招募妇女，从而最大限度地减少数据收集和抽样中的偏差。丹麦的这项研究从怀孕的头三个月开始跟踪调查了96000多名妇女，并对母亲和孩子的结局有广泛的生物学和流行病学数据。在这个提议中，我们将使用1000例非常典型的自发性早产病例进行全基因组病例/对照分析，并从丹麦国家出生队列研究中提取母亲和婴儿的生物样本。这些将与1000名怀孕39或40周出生的母亲/婴儿对照。广泛的流行病学变量将被用作分析中的协变量。为了重复积极的发现，我们可以从丹麦国家出生队列研究中获得更多的控制资源，以及从美国大量样本收集中获得的1000多名母亲/父亲/早产儿三位一体，以及另外1000名美国非裔美国人的病例/对照，非洲裔美国人的早产率很高。涉及环境因素的阳性结果可以进一步调查，因为丹麦队列有妊娠早期和中期的母体血清样本，以及其他流行病学和结局数据。这项研究应该能够更好地理解分娩生物学，确定在早产中起作用的共同遗传因素，并提出可以延长妊娠期的环境改变，以改善新生儿和成人的结局。

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.