OF RESEARCH PLANThe overall goal of Project I is to determine the extent and distribution of sequence variation incandidate genes in the maternal-placental-fetal (MPF) endocrine pathway of pregnancy and prematurebirth. Although the precise genetic factors that influence premature birth have not yet been identified, theimportance of genetics is indicated by familial aggregation, differences in prevalence among racial/ethnicgroups, and molecular genetic studies that have identified significant associations with DMA polymorphismsin candidate genes of parturition. Previous studies have shown large disparities in the prevalence ofpremature birth across racial/ethnic groups, likely due to both genetic and environmental factors. Project Iwill contrast patterns of variation in 16 candidate genes for each of three major racial/ethnic groups (AfricanAmericans, Hispanics of Mexican Origin, and non-Hispanic Whites). We will identify sequence variations(SNPs) and directly determine SNP haplotypes for each of three racial/ethnic groups by resequencing inhaploid cell lines that separately contain maternal and paternal chromosomes (molecular haplotyping). TheSNPs we identify in Project I will be genotyped in the 1,200 mother-child pairs by Core C for subsequentpopulation genetic analyses.
The specific aims are:
Aim 1 : Resequence 16 candidate genes in the maternalplacental-fetal (MPF) neuroendocrine pathway to identify and characterize the distribution of DMAsequence variations (SNPs) within and among samples of individuals representative of three localpopulations: African-American, Hispanic of Mexican origin, and non-Hispanic Whites.
Aim 2 : Model and testhypotheses about the structure of the variation in the 16 candidate genes to establish which alleles, whichhaplotypes, and which genotypes of which genes vary within and between which of the three racial/ethnicsamples. The underlying causes of racial/ethnic disparities in the prevalence of premature birth in the UnitedStates are not well-understood. We and others have recently discovered significant racial/ethnic differencesin the biology of the maternal-placental-fetal neuroendocrine system over the course of gestation. Bydetermining the population structure of genetic variation in the three major racial/ethnic groups, this projectwill make an important contribution to our understanding of the extent to which the observed racial/ethnicdifferences in biology and clinical outcome (premature birth) reflect differences in genetic variation ordifferences that arise from altered expression of the same genes and variants as a consequence ofracial/ethnic differences in environmental conditions/triggers.
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