Role of Cytokines and Promoter Genotype in Prematurity

描述（由申请人提供）：假设：妊娠早期下生殖道促炎细胞因子浓度降低表明对上升的微生物入侵更敏感。妊娠早期子宫颈细胞因子的增加表明先前存在的上升微生物入侵。与白人妇女相比，非洲裔美国妇女在怀孕早期更有可能在下生殖道中出现极端浓度（或低或高）的细胞因子，从而导致早产率增加。这些种族差异可以用环境因素和细胞因子启动子遗传多态性的影响来解释。评估孕前细胞因子、子宫内膜组织学和细胞因子启动子表型将有助于我们确定孕前上生殖道感染是否会增加下生殖道细胞因子并增加早产的风险。具体目的：评估妊娠早期下生殖道促炎因子（IL-1 β、IL-6、IL-8和tnf - α）和抗炎/调节因子（IL-4、IL-10、IL-1受体拮抗剂、tnf - α可溶性受体和TGFBeta1）浓度与随后早产的关系；探讨种族对妊娠早期下生殖道促炎产物和抗炎产物浓度的影响；按种族评估环境因素和细胞因子启动子遗传多态性对下生殖道促炎产物和抗炎产物浓度的影响；探讨孕前组织学子宫内膜炎与促炎细胞因子启动子表型、孕前和孕中生殖细胞因子水平及早产的关系。方法：为了充分研究细胞因子浓度与不良妊娠结局之间的复杂关系，我们将对400名白人和400名非裔美国妇女进行观察性、前瞻性、纵向研究，这些妇女在马吉妇女医院产前诊所接受产前护理。在16和26周孕龄时，将获得血液和宫颈标本，用于测量细胞因子启动子基因多态性、生殖器细胞因子产生和生殖器细菌。访谈和生物学测量将用于评估早产的流行病学危险因素。另一个小队列（n=200）的妇女将被招募，以显示怀孕前上生殖道子宫内膜炎、细菌感染、怀孕早期生殖器细胞因子测量、促炎细胞因子启动子表型和早产风险之间的关系。

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.