Preterm delivery (PTD, less than 37 weeks of gestation) is the single most important cause of perinatal mortality and the most important child health problem in developed countries. The etiology of PTD is unclear, but both genetic and environmental factors appear to play a role. The central scientific hypothesis of this proposal is that the polymorphisms of candidate genes in the 4 pathogenic pathways of PTD and metabolic detoxification genes, or the expression levels of certain genes in the placenta at delivery, are associated with PTD either independently or through interactions with environmental exposures. Due to the exploratory nature of this proposal, its major focus is to enhance collaborations among scientists working in the fields of epidemiology, environmental health sciences, molecular biology, and biostatistics; and to establish and strengthen capacities to apply high throughput genotyping and microarray technology as well as innovative statistical methods in molecular epidemiologic study of PTD. This proposal is built on the investigators' ongoing molecular epidemiologic studies of PTD in diverse populations. They have formed a multidisciplinary team; accumulated considerable field, laboratory, and analytical experiences; and generated promising preliminary data. In the process, they have also encountered a number of methodological issues. This NIH grant will provide the necessary resources to address the major methodological challenges.
The specific aims are: (1) to apply high throughput technologies to genotype the proposed candidate genes using stored maternal and cord blood samples; (2) to apply microarray technology to obtain profiles of gene expression in stored placental specimens of preterm and term delivery; (3) to apply and develop innovative statistical methods to analyze data generated from high throughput genotyping and microarray analysis; and (4) to determine frequency distributions of polymorphisms of proposed candidate genes. The investigators will test the proposed technology and methodology in 24 preterm (cases) and 24 term (controls) mother-infant pairs from their existent population at Boston Medical Center (BMC), a predominantly inner city, high risk, multi-ethnic population, with a high prevalence of cigarette smoking. The success of this proposed study will lead to new approaches to understand the role of genetic susceptibility and gene-environment interactions in the pathogenesis of PTD in the BMC population and in other U.S. populations. As shown in D.2 and D.3 of the proposal, the research team not only possesses technical and intellectual capability and relevant experiences to carry out the proposed study, but also has a tracking record of successful and productive multidisciplinary collaboration in molecular reproductive epidemiology.
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