Identification of maternal and fetal genetic factors in preterm birth

描述（由申请人提供）：早产，或在妊娠37周前分娩婴儿，是早产的结果，它影响了全球约10%的妊娠，在美国，这一数字正在增长，现在为12%。尽管技术进步，早产导致大量的发病率和死亡率高达80%的婴儿出生前33周的妊娠在发展中国家。存活的婴儿有很高的认知迟缓、脑瘫、慢性肺病、失明和耳聋的比率。这一问题的严重性对穷人和少数群体的影响尤为严重，对个人、家庭和社会的影响是毁灭性的，迫使人们对病因进行调查，从而可能改善治疗和预防。虽然早产的一些具体原因是公认的，如双胎妊娠和宫颈机能不全，大多数是“自发的”。潜在的引发因素包括感染、营养不良和遗传因素。双胞胎和家庭研究表明，遗传因素是这种风险的40%，早产的最佳预测因素是以前的早产。虽然有许多方法可以确定复杂性状（如早产）的因果机制，但遗传学研究不仅可以验证先前怀疑的病因，还可以确定意料之外的因素。 研究早产遗传因素的一个主要挑战是，风险病例没有明确定义，因为它可能是母亲和她的子宫，婴儿/胎盘单位，或两者兼而有之。我们已经组建了一个包括产科医生，儿科医生，定量遗传学家和分子生物学家在内的研究团队，以采取全面的方法来确定早产的遗传原因。我们将使用一个家庭收集计划，其中婴儿或母亲可以作为一个潜在的情况下，一个强大的三代收集方法，加上全基因组搜索，以确定一些可能有助于早产及其次要结果的多个基因。我们的团队已经合作多年，并将利用我们在临床确定，分子遗传学和基因鉴定统计方法方面的丰富经验。具体目标包括：案件的查明和定性。二.候选基因评估。三.利用连锁和连锁不平衡进行全基因组扫描。四.用于基因鉴定的精细定位。其结果将是确认（或拒绝）以前怀疑的因素，确定新的遗传贡献，并建立一个平台，使我们能够快速进入环境协变量，生物机制和预防和治疗临床试验的研究。

DESCRIPTION (provided by applicant): Premature birth, or the delivery of an infant before 37 weeks gestation, is the result of preterm labor and it affects approximately 10% of pregnancies world-wide with growing numbers now at 12% in the United States. In spite of advances in technology, prematurity results in substantial morbidity and mortality as high as 80% in infants born earlier than 33 weeks gestation in developing countries. Surviving infants have high rates of cognitive delay, cerebral palsy, chronic lung disease, blindness and deafness. The enormity of this problem, which disproportionately affects the poor and minority groups, is devastating in its impact on individuals, families, and society and compels investigations into etiologies that may lead to improvements in treatment and prevention. While some specific causes of prematurity are recognized, such as twin pregnancies and cervical incompetence, the majority are "spontaneous". Potential initiators include infection, poor nutrition, and inherited factors. Twin and family studies suggest that genetic factors underlie 40% of this risk and the single best predictor for preterm delivery is a previous preterm birth. While there are many approaches to identifying causal mechanisms in complex traits such as prematurity, genetic investigations afford the opportunity to not only validate previously suspected etiologies but to identify unanticipated factors. A major challenge in studying genetic factors in prematurity is that the risk case is not explicitly defined as it might be either the mother and her uterus, the infant/placental unit, or the two together. We have assembled a team of investigators including obstetricians, pediatricians, quantitative geneticists, and molecular biologists to undertake a comprehensive approach to identify genetic causes of prematurity. We will use a family collection scheme in which either the infant or the mother can be studied as a potential case and a powerful three generation collection approach coupled to genome-wide searches to identify some of the multiple genes likely contributing to prematurity and its secondary outcomes. Our group has worked together for many years and will use our extensive experience in clinical ascertainment, molecular genetics and statistical approaches for gene identification. Specific aims include: I. Case identification and characterization. II. Candidate gene evaluation. III. Genome-wide scans using both linkage and linkage disequilibrium. IV. Fine-mapping for gene identification. The outcome will be confirmation (or rejection) of previously suspected factors, identification of new genetic contributions, and the establishment of a platform that will enable us to move quickly into studies of environmental covariates, biological mechanisms and clinical trials for prevention and treatment.