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周之前分娩婴儿，是早产的结果，它影响了全世界约10%的怀孕，目前在美国这一数字正在增长，为12%。尽管技术取得了进步，但在发展中国家，早产导致妊娠早于33周出生的婴儿的发病率和死亡率高达80%。幸存的婴儿认知迟缓、脑瘫、慢性肺病、失明和耳聋的发病率很高。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。虽然一些特殊的早产原因是公认的，如双胎妊娠和宫颈功能不全，但大多数是“自发的”。潜在的诱发因素包括感染、营养不良和遗传因素。双胞胎和家庭研究表明，遗传因素占这种风险的40%，而以前的早产是早产的唯一最佳预测因素。虽然有许多方法可以确定复杂特征（如早产）的因果机制，但遗传调查不仅可以验证先前怀疑的病因，还可以确定意想不到的因素。

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.