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.
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