Role of Cytokines and Promoter Genotype in Prematurity

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DESCRIPTION (provided by applicant): Hypotheses: Decreased concentrations of pro-inflammatory cytokines in the lower genital tract early in pregnancy indicate a greater susceptibility to ascending microbial invasion. Increased cytokines in the cervix early in pregnancy indicate pre-existing ascending microbial invasion. African-American women are more likely to have extreme concentrations (lower or higher) of cytokines in the lower genital tract early in pregnancy compared with white women resulting in their increased rate of preterm delivery. These racial differences are explained by the effect of both environmental factors and cytokine promoter genetic polymorphisms. Evaluating the pre-pregnant cytokines, endometrial histology, and cytokine promoter phenotype will help us determine whether pre-pregnant upper genital tract infection raises lower genital tract cytokines and increases the risk of preterm delivery. Specific Aims: To assess the relationship of concentration of pro-inflammatory cytokines (IL-1Beta, IL-6, IL-8, and TNF-alpha) and anti-inflammatory/regulatory cytokines (IL-4, IL-10, IL-1 receptor antagonist, TNF-alpha soluble receptor, and TGFBeta1) in the lower genital tract early in pregnancy with subsequent preterm birth; To evaluate the effect of race on concentration of pro- and anti-inflammatory products in the lower genital tract early in pregnancy; To assess, by race, the impact of environmental factors and cytokine promoter genetic polymorphisms on the concentration of pro- and anti-inflammatory products in the lower genital tract; To evaluate the relationship of pre-pregnancy histologic endometritis with proinflammatory cytokine promoter phenotype, genital cytokine levels before and during pregnancy, and preterm delivery. Methods: To fully investigate the intricate relationship between cytokine concentrations and adverse pregnancy outcome we will perform an observational, prospective, longitudinal study of 400 white and 400 African-American women seeking prenatal care from Magee-Women's Hospital antepartum clinics. Blood and cervical specimens will be obtained for the measurement of cytokine promoter gene polymorphisms, genital cytokine production, and genital bacteria at 16 and 26 weeks gestational age. Interview and biologic measures will be used to assess epidemiologic risk factors for preterm birth. An additional small cohort (n=200) of women will be enrolled to show the relationship between pre-pregnant upper genital tract endometritis, bacterial infection, genital cytokines measured early in pregnancy, proinflammatory cytokine promoter phentoype, and the risk of preterm birth.