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.
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.
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