A Family and Population Approach to Gene Discovery for Preterm Birth

描述（由申请人提供）：早产是一个复杂的问题，对个人、家庭和社会都有毁灭性的影响。在过去20年中，发达国家的早产发生率稳步上升，全世界每年有300多万儿童死于早产。尽管这一问题很重要，而且在穷人和少数民族人口中发生率过高，但很难确定其根本原因。自然早产被怀疑会引发感染、压力、营养不良和遗传因素。早产的唯一最佳预测指标是以前的早产。对双胞胎和家族内复发的研究提供了证据，证明遗传因素是早产风险的实质性组成部分。研究早产遗传因素的一个主要挑战是风险案例尚未真正确定。遗传风险可能存在于母亲及其子宫或婴儿/胎盘中。确定母亲和/或婴儿的遗传因素可以为确定相关的环境协变量提供见解，这些协变量可能更适合快速干预，但仅使用标准流行病学很难找到。一个全面的全基因组关联研究（GWAS）是一种理想的方法来识别那些基于我们目前对分娩生物学的理解而不会被怀疑的基因。我们正在使用4000个生物样本和详细的环境数据，这些数据来自丹麦的一项前瞻性队列研究，该研究在早产发生前收集了1000对母亲/婴儿。这使得对环境风险的有力评估将与资助的全基因组关联研究相匹配，以全面评估导致早产的基因/环境相互作用。第二组收集了2200多个非裔美国人的早产样本，也正在进行全基因组关联测试。这些研究的GWAS阶段已经得到资助并正在进行中，该提案将为开展这两个关键种群的基本复制和精细绘图研究提供资源。我们已经有4000对丹麦早产儿的样本用于复制，本次提案将收集非洲裔美国人的样本用于复制，进行复制基因分型，并分析和精细绘制与环境变量耦合的输出。这一结果将有助于更好地理解分娩生物学，并建议改变环境，延长妊娠期，以改善新生儿和成人的结局。

DESCRIPTION (provided by applicant): Preterm delivery resulting in the birth of a premature infant is a complex problem with a devastating impact on individuals, families and society. The prevalence of preterm birth has increased steadily in developed countries over the last 20 years and more than three million children die of preterm birth worldwide each year. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, the underlying causes have been difficult to identify. Spontaneous preterm labor has as its suspected triggers infection, stress, poor nutrition and inherited factors. The single best predictor for preterm delivery is a previous preterm birth. Studies of twins and of recurrences within families provide evidence that genetic factors underlie a substantive component of the risk for prematurity. One major challenge in studying genetic factors in prematurity is that the risk case is not truly established. The genetic risk could reside either in the mother and her uterus or in the infant/placenta. Identification of genetic factors in the mother and/or infant could provide insights into identifying relevant environmental covariates that may be more amenable to rapid interventions but difficult to find using standard epidemiology alone. A comprehensive genome-wide association study (GWAS) is the ideal way to identify those genes that would not be suspected based on our current understanding of the biology of parturition. We are using 4000 biological samples and detailed environmental data from a prospective cohort study in Denmark that has 1000 mother/infant pairs collected before the onset of preterm labor. This enables a powerful assessment of environmental risks that will be matched to a funded genome-wide association study in a comprehensive assessment of gene/environment interactions contributing to preterm birth. A second collection of over 2200 African American samples with preterm labor is also undergoing genome- wide association testing. The GWAS phase of these studies is already funded and underway and this proposal will provide the resources to carry out the essential replication and fine mapping studies of these two key populations. We already have samples for 4000 Danish preterm birth pairs for replication and in this proposal will collect African American samples for replication, carry out replication genotyping, and analyze and fine map the output coupled to environmental variables. The result will enable a better understanding of the biology of parturition and suggest environmental modifications that can prolong gestations to improve neonatal and adult outcomes. PUBLIC HEALTH RELEVANCE: Prematurity is perhaps the single greatest contributor to mortality and morbidity in the world today with more than five million children that will die worldwide of preterm delivery complications in the next year. Identification of the underlying causes of prematurity, and particularly gene environment interactions, affords tremendous promise for identifying both more effective treatment strategies as well as preventive measures that could have enormous public health benefits.