This Program Project, entitled Gene-Environment Interactions in Human Parturition, proposes to evaluate the utility of information about DMA sequence variation and function in candidate susceptibility genes to understand and predict the risk of preterm birth and racial/ethnic disparities in its prevalence. Our goal is to develop a genotype/phenotype resource and analytical strategies to identify the genetic and environmental determinants of the length of human gestation/ tinning of onset of spontaneous parturition, and to model the gene, environment, and maternal-fetal interactions that may underlie the risk of preterm birth among three racial/ ethnic populations: African-Americans, Hispanics and nonHispanic Whites. The genetic architecture of parturition is defined as the number of loci, their genomic positions, the number of functional alleles per locus, and the patterns of dominance, epistasis, pleiotropy, and geneenvironment interactions that characterize the transition from genotype to phenotype. Because the genetic architecture of parturition may vary among populations as a function of the heterogeneity of the relative frequencies of genetic and environmental effects, population-specific models will be developed in our analysis. Our research program will consist of three separate but inter-linked projects that propose and empirically test hypotheses, and four cores that provide the requisite resources for each of the projects. Project 1 - Population Structure of Genetic Variation in Pregnancy (James Hixson, PI) - will determine the full extent and distribution of genetic variation in the 16 candidate genes of interest among and between the three target racial/ethnic populations. Project 2 - Genotype- Phenotype Relationships in Human Parturition (Charles F. Sing, PI)- will examine genotype-phenotype associations to determine which subset of fetal and maternal genetic variations, in combination with specific environmental factors, predict measures of intermediate physiology and clinical end points in each of the three target racial/ethnic populations. Project 3 - Functional Significance of Genetic Variation in Pregnancy (Pathik D. Wadhwa, PI) - will characterize the functional relationships between maternal and fetal genetic variation and the dynamics of parturitionand stress-related physiological processes in vivo. The four cores are A) Administrative Core (Pathik Wadhwa, Director), to serve as an administrative office for the central co-ordination of all project and core activities (will include an Executive Committee and Internal and External Advisory Boards); B) Clinical Core (Calvin J. Hobel, Director) to collect clinical measures on 1,200 maternal-infant dyads, including DNA samples and measures of intermediate physiology, clinical end points and environmental risk factors; C) Genotyping Core (James E. Hixson, Director) to extensively resequence the 16 candidate genes and genotype 1,200 maternal-fetal DNA samples and unlinked genomic control polymorphismic markers; and D) Database Management and Statistical Analysis Core (Charles F. Sing, Director) to maintain a central study database and execute statistical analyses for all projects. ? ? ?
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