IDENTIFICATION OF MATERNAL AND FETAL GENETIC FACTORS IN PRETERM BIRTH

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。早产，或在妊娠37周之前分娩婴儿，是早产的结果，它影响了全球约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，但早产仍然导致发病率和死亡率居高不下，在美国，每1 000名活产婴儿中有7人在出生后第一个月内死亡。在欠发达国家，即使在妊娠32周出生的婴儿死亡率也高达80%。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、早产、产前胎膜破裂和宫颈功能不全，但仍有很大一部分原因被认为是自发的。潜在的诱发因素包括感染、压力、营养不良、药物滥用、代谢失衡和遗传因素。双胞胎研究表明，遗传因素占这种风险的40%，而早产的唯一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特征（如早产）的因果机制，但遗传调查不仅提供了验证先前怀疑的病因的机会，而且还提供了识别以前未预料到的全新因素的机会。研究早产遗传因素的一个主要挑战是风险病例尚未确定，因为它可能是母亲和她的子宫，婴儿胎盘单位，或两者一起，这使得即使是基本的病例对照研究也难以进行。这些研究人员组建了一个跨学科的研究团队，包括产科医生、儿科医生、定量遗传学家和分子生物学家，他们采用了一种全面的遗传方法来确定早产的潜在遗传原因。他们将使用一个全面的家庭收集计划，其中婴儿或母亲都可以作为潜在病例进行研究，并将标准的候选基因研究与非常强大的三代病例-父母三合一方法结合起来，利用全面的全基因组搜索来识别可能导致早产的多种基因。然后，基因鉴定可以为潜在生物学机制的研究提供支持，确认旧靶点，最重要的是，确定预防和治疗策略的新靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 continued high-rates of morbidity and mortality with 7 per 1,000 live-born infants dying in the first month of life in the United States. Mortality is as high as 80% in infants born even at 32 weeks gestation in less developed countries. The enormity of this problem which disproportionately affects the poor and minority groups, is devastating in its impact on individuals, families, and society, 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, preterm pre-labor rupture of membranes, and cervical incompetence, a large group remains which can be considered spontaneous. Potential initiators of this include infection, stress, poor nutrition, substance abuse, metabolic imbalances, and inherited factors. Twin 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 entirely new factors not previously anticipated. A major challenge in studying genetic factors in prematurity is that the risk case is not yet established as it might be either the mother and her uterus, the infant placental unit, or the two together, and this makes even basic-case control studies difficult to undertake. These investigators have assembled a team of interdisciplinary investigators including obstetricians, pediatricians, quantitative geneticists, and molecular biologists to undertake a comprehensive genetic approach to identifying underlying genetic causes of prematurity. They will use a comprehensive family collection scheme in which either the infant or the mother can be studied as potential cases and incorporate standard candidate gene studies coupled to a very powerful three generation case-parent triad approach utilizing comprehensive genome-wide searches to identify the multiple genes likely contributing to prematurity. Gene identification can then serve to feed studies of underlying biological mechanisms, confirm old targets and, most importantly, identify new targets for prevention and treatment strategies.