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Preterm Birth: Causes, Consequences, and Prevention
Sciences initiated the Environmental Genome Project (EGP) in 1998 to identify polymorphisms in the genes involved in environment-induced diseases (Olden and Wilson, 2000). In addition to the identification of polymorphisms, EGP aims to characterize the functions of these polymorphisms and supports epidemiological studies of gene-environment interactions.
Studies Involving One or a Few Candidate Genes
To date, most published studies on the genetics of preterm birth have examined only one or a few genes in a given study sample. The frequent association of spontaneous preterm labor and preterm birth with histological infection-inflammation and elevated concentrations of inflammatory cytokines in body fluids has focused investigations on single gene polymorphisms in the genes for these cytokines in both the mother and the fetus (Varner and Esplin, 2005), as it has been well established that upper genital tract infections and inflammation are associated with spontaneous preterm labor and preterm birth (Goldenberg and Andrews, 1996). The polymorphisms examined include those in the genes for the cytokines tumor necrosis factor alpha (TNF-α) nucleotide 308 (Dizon-Townson et al., 1997; Roberts et al., 1999), interleukin-1β (IL-1β) nucleotides 3953 and 3954 (Genc et al., 2002), and IL-6 nucleotide 174 (Jamie et al., 2005; Simhan et al., 2003); but the findings of an association of polymorphisms in these genes and preterm birth have been inconsistent.
Other studies have examined the roles of SNPs in preterm labor and preterm birth. Toll-like receptors, which are important components of the innate immune system, have been linked to spontaneous preterm labor and preterm birth (Lorenz et al., 2002). Gene polymorphisms in matrix metalloproteineases (MMPs) and preterm premature rupture of membranes (PPROM) were examined in African Americans. The breakdown of the interstitial collagens is mediated by MMPs. A fetal genotype of a mutation in the gene for matrix metalloproteinease type 1 (MMP-1) was found in association with PPROM (Fujimoto et al., 2002). Three SNPs located at positions –799 C to T), –381 (A to G), and +17 (C to G) (where C, T, A, and G represent the nucleotides cytosine, thymine, adenine, and guanine, respectively) from the major transcription start site in the MMP-8 gene have been identified; and the functional significance of SNP haplotypes in the MMP-8 gene and associations with PPROM has been demonstrated (Wang H et al., 2004). MMP-8 is an enzyme that degrades fibrillar collagens and that imparts strength to the fetal membranes; it is expressed by leukocytes and chorionic cytotrophoblast cells. There are cell host-dependent differences in MMP-9 promoter activity related to CA-repeat number and fetal carriage of the 14 CA-repeat allele is associated with PPROM in African Americans (Ferrand et al., 2002). Finally, a study (Ozkur et al., 2002) found that a