Role of Cytokines and Promoter Genotype in Prematurity

描述(由申请人提供)：假设：在怀孕早期，下生殖道中促炎症细胞因子的浓度降低，表明更容易受到向上的微生物入侵。妊娠早期宫颈中细胞因子的增加表明先前存在上升的微生物入侵。与白人妇女相比，非裔美国妇女在怀孕早期下生殖道中细胞因子的极端浓度(低或高)更有可能导致她们早产率的增加。这些种族差异是由环境因素和细胞因子启动子基因多态共同作用的结果。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：探讨妊娠早期下生殖道促炎症细胞因子(IL-1β、IL-6、IL-8、TNF-α)与抗炎/调节性细胞因子(IL-4、IL-10、IL-1受体拮抗剂、肿瘤坏死因子-α可溶性受体、TGFBeta1)浓度的关系，以及种族对妊娠早期下生殖道促炎、抗炎产物浓度的影响；通过RACE方法，评估环境因素和细胞因子启动子基因多态性对下生殖道促炎和抗炎产物浓度的影响；评估孕前组织学子宫内膜炎与促炎细胞因子启动子表型、孕前和孕期生殖器细胞因子水平及早产的关系。方法：为了全面调查细胞因子浓度和不良妊娠结局之间的复杂关系，我们将对400名白人和400名非洲裔美国妇女进行观察性、前瞻性、纵向研究，这些妇女在Magee-Women‘s医院产前诊所寻求产前护理。将在16周和26周时采集血液和宫颈样本，用于测量细胞因子启动子基因的多态、生殖器细胞因子的产生和生殖器细菌。将使用访谈和生物措施来评估早产的流行病学危险因素。另外一组妇女(n=200)将被纳入，以显示孕前上生殖道子宫内膜炎、细菌感染、妊娠早期测量的生殖器细胞因子、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.