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A Family and Population Approach to Gene Discovery for Preterm Birth

早产基因发现的家庭和人群方法

基本信息

批准号：
8071963
负责人：
JEFFREY C MURRAY
金额：
$ 57.6万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-03 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071963
关键词：
Adult African American Alleles Biological Biology Birth Candidate Disease Gene Child Cohort Studies Collection Complex Coupled Data Denmark Dependence Developed Countries Environment Environmental Risk Factor Epidemiology Family Funding Genes Genetic Genetic Predisposition to Disease Genetic Risk Genotype Health Benefit Heterogeneity Individual Infant Infection Intervention Investigation Maps Masks Measures Minority Modification Morbidity - disease rate Mothers Neonatal Outcome Output Phase Placenta Population Pre-Eclampsia Pregnancy Premature Birth Premature Infant Premature Labor Prevalence Preventive Public Health Recurrence Resources Risk Sampling Societies Stress Testing Twin Multiple Birth Twin Studies Uterus Variant base cohort disability effective therapy gene discovery gene environment interaction genetic risk factor genome wide association study genome-wide high risk human mortality improved insight mortality nutrition premature prospective public health relevance treatment strategy

项目摘要

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.

描述（由申请人提供）：早产导致早产儿的出生是一个复杂的问题，对个人，家庭和社会产生破坏性影响。在过去的20年里，早产的流行率在发达国家稳步上升，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的发生率不成比例，但其根本原因一直难以查明。自发性早产可能是感染、压力、营养不良和遗传因素的触发因素。早产的唯一最佳预测因素是以前的早产。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，风险病例尚未真正确定。遗传风险可能存在于母亲及其子宫或婴儿/胎盘中。在母亲和/或婴儿的遗传因素的识别可以提供洞察力，以确定相关的环境协变量，可能更适合快速干预，但很难找到单独使用标准流行病学。一个全面的全基因组关联研究（GWAS）是一个理想的方法来确定那些基因，不会被怀疑基于我们目前的理解分娩的生物学。我们正在使用来自丹麦的一项前瞻性队列研究的4000份生物样本和详细的环境数据，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能够与资助的全基因组关联研究相匹配，全面评估导致早产的基因/环境相互作用。第二次收集的2200多名早产的非洲裔美国人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，该提案将提供资源，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4000丹麦早产对复制的样本，并在本提案中将收集非裔美国人样本进行复制，进行复制基因分型，并分析和精细映射输出耦合到环境变量。该结果将使人们能够更好地了解分娩的生物学，并建议进行环境改造，以延长妊娠期，从而改善新生儿和成人的结局。公共卫生关系：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。识别早产的根本原因，特别是基因环境相互作用，为确定更有效的治疗策略以及可能具有巨大公共卫生效益的预防措施提供了巨大的希望。