A Family and Population Approach to Gene Discovery for Preterm Birth

描述(申请人提供)：早产导致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，发达国家的早产患病率稳步上升，全世界每年有300多万儿童死于早产。尽管这一问题很重要，而且在穷人和少数群体中不成比例地发生，但其根本原因一直难以确定。自然早产被怀疑是感染、压力、营养不良和遗传因素的触发因素。早产的唯一最好的预测因素是先前的早产。对双胞胎和家庭内复发的研究提供了证据，表明遗传因素是早产风险的实质性组成部分。研究早产儿遗传因素的一个主要挑战是风险案例尚未真正确立。遗传风险可能存在于母亲和她的子宫或婴儿/胎盘中。识别母亲和/或婴儿的遗传因素可为确定相关环境协变量提供洞察力，这些协变量可能更容易受到快速干预，但仅使用标准流行病学很难找到这些协变量。根据我们目前对分娩生物学的理解，全面的全基因组关联研究(GWAS)是识别那些不会被怀疑的基因的理想方法。我们使用了来自丹麦一项前瞻性队列研究的4000个生物样本和详细的环境数据，该研究在早产开始之前收集了1000对母婴。这使得能够对环境风险进行强有力的评估，这将与一项资助的全基因组关联研究相匹配，在对导致早产的基因/环境相互作用的全面评估中。第二批2200多名早产的非裔美国人样本也正在接受全基因组关联测试。这些研究的全球气候变化研究阶段已经得到资助并正在进行中，这项提议将提供资源，以便对这两个关键人群进行必要的复制和精细绘图研究。我们已经有了4000对丹麦早产夫妇的样本进行复制，在这项提议中，我们将收集非裔美国人的样本进行复制，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。这一结果将使人们更好地理解分娩的生物学，并提出可以延长妊娠以改善新生儿和成人结局的环境调整建议。 公共卫生意义：早产可能是当今世界死亡率和发病率的最大因素，明年全世界将有500多万儿童死于早产并发症。确定早产的根本原因，特别是基因环境的相互作用，为确定更有效的治疗战略和预防措施提供了巨大的希望，这些措施可能会对公众健康产生巨大的好处。

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.