Epigenetic Determinants and Mechanisms Influencing Genital Chlamydia trachomatis Reinfection in African American Women

摘要：沙眼衣原体（Ct）感染是最常见的性传播细菌 感染世界。仅在美国，估计每年就有300万例衣原体感染病例。 女性的Ct上升感染可导致盆腔炎（PID），导致生殖系统疾病。 后遗症如宫外孕、不孕症和慢性盆腔疼痛。Ct感染也会引起 非裔美国人，他们的Ct感染率几乎是白人的6倍。Ct感染率仍然 尽管采取了积极的预防和控制措施，但感染率仍然很高，20%的确诊患者在一年内再次感染， 这表明一些感染者没有产生足够的免疫保护。再次感染有助于 持续的Ct传播和Ct感染后遗症的风险。更好的预防措施，如疫苗， 是必要的。开发Ct疫苗以及其他预防和控制Ct感染的措施， 人类一直受到阻碍，部分原因是对免疫机制的不完全理解， 保护人类免受Ct感染。本申请中提出的研究目标是确定 表观遗传改变影响免疫反应和Ct再感染风险。几项研究表明 单个CpG位点的DNA甲基化变异具有很强的遗传成分。基因对DNA的影响 甲基化变异可以部分地通过位于靶CpG位点附近的SNP来解释。遗传 与甲基化变异相关的变异通常被称为甲基化数量性状 基因座（meQTL）是理解基因型-性状关联的表观遗传机制的关键。 从现有免疫阵列中获得的DNA变体，以及从本提案中获得的DNAm分析， 将允许理解免疫遗传机制，有助于Ct再感染的发病机制。 中心假设：我们假设改变的表观遗传变异影响对Ct的免疫应答， 因此Ct再感染的风险也很大。此外，我们假设，确定连锁遗传和表观遗传， 影响免疫反应和Ct再感染风险的变异将使我们能够确定功能性 免疫遗传机制在目标1中，我们将进行表观遗传广泛关联分析（EWAS），以确定 非洲人免疫应答介导抗Ct再感染保护作用的表观遗传变异 美国女人在目标2中，我们将使用表观遗传，遗传和免疫反应数据来模拟它们如何在体内表达。 影响Ct再感染风险。总之，我们的研究将调查调节 免疫应答和影响Ct再感染风险。据我们所知，这些将是第一次研究 人类Ct感染的表观遗传学。我们希望我们的研究将推进关于表观遗传和遗传 影响免疫应答和Ct再感染风险的因素，这将促进靶向免疫治疗的发展。 干预措施，如疫苗，以预防和控制Ct感染。

Summary/Abstract: Chlamydia trachomatis (Ct) infection is the most prevalent sexually transmitted bacterial infection in the world. In the US alone, an estimated 3 million chlamydia cases are expected to occur annually. Ascending Ct infection in women can lead to pelvic inflammatory disease (PID), resulting in reproductive sequelae such as ectopic pregnancy, infertility, and chronic pelvic pain. Ct infections also disproportionally affect African Americans, who have almost a 6-fold higher Ct infection rate than Caucasians. Ct infection rates remain high despite active prevention and control efforts, and 20% of diagnosed patients are re-infected within one year, suggesting some infected persons do not develop sufficient immune protection. Reinfection contributes to continued Ct transmission and risk for Ct infection sequelae. Better prevention measures, such as a vaccine, are needed. The development of a Ct vaccine as well as other measures to prevent and control Ct infection in humans have been hindered in part by an incomplete understanding of the immune mechanisms that contribute to protection against Ct infections in humans. The goal of the research proposed in this application is to identify epigenetic alterations that influence immune responses and Ct reinfection risk. Several studies have shown that DNA methylation variation at individual CpG site has strong genetic component. The genetic effects on DNA methylation variations can be explained, in part, by SNPs located in close vicinity of the target CpG sites. Genetic variants that are associated with methylation variation are commonly referred to as methylation quantitative trait loci (meQTL), are crucial for understanding the epigenetic mechanisms underlying genotype-trait associations. DNA variants available from an existing ImmunoArray, together with DNAm profiling available from this proposal, will allow understanding of immunogenetic mechanisms that contribute to the pathogenesis of Ct reinfection. Central hypothesis: We hypothesize that altered epigenetic variation affects the immune response to Ct and therefore the risk for Ct reinfection. Furthermore, we hypothesize that identifying linked genetic and epigenetic variants that influence immune responses and Ct reinfection risk will allow us to pinpoint functional immunogenetic mechanisms. In Aim 1, we will conduct Epigenetic-Wide Association Analysis (EWAS) to identify epigenetic variations associated with immune responses that mediate protection against Ct reinfection in African American women. In Aim 2, we will use epigenetic, genetic, and immune response data to model how they influence Ct reinfection risk. In summary, our studies will investigate epigenetic mechanisms that modulate immune responses to Ct and influence Ct reinfection risk. To our knowledge, these will be the first studies of epigenetics in human Ct infection. We expect our studies will advance knowledge on how epigenetic and genetic factors influence immune responses and Ct reinfection risk, which should advance development of targeted interventions, such as a vaccine, to prevent and control Ct infection.