Association of Fetal Genotypes with Cytokine Levels and Preterm Birth

 描述(由申请人提供)：早产(PTB)相关疾病是围产期发病率和死亡率的主要原因。炎症与这些疾病有很强的相关性；细胞因子是炎症的标志。一些研究表明，胎儿的基因分型可能参与胎儿-母体交界处的炎症反应，这可能与胎膜破裂、自发性肺结核和胎儿损伤有关。虽然已发现母体基因与肺结核相关疾病之间的关联，但很少有研究检查和确定与肺结核相关的发病率和死亡率密切相关的胎儿基因，而那些已显示出适度相关性的研究需要验证/复制。因此，拟议的调查的主要目的是确定与肺结核相关结局风险较高的胎儿基因变异，并 找出解释这种联系的细胞因子。通过识别高危新生儿，拟议的分析将加强对导致肺结核相关结局的病理生理学和生物学机制的理解，并提出干预策略。利用新生儿研究网络(NRN)的现有数据，拟议的计划将涉及对1030个样本进行分析，这些样本包含23种细胞因子在5个时间点的全基因组基因数据和蛋白质表达数据。这项研究的具体目的是(1)描述可能与肺结核相关结局相关的炎性级联遗传标志物及其相关细胞因子蛋白表达水平之间的关系，以及(2)调查所研究的遗传标志物和细胞因子中是否有任何遗传标志物和细胞因子表明肺结核相关结局的不同风险。这项研究的结果应该能够完整地描述细胞因子遗传标记、细胞因子蛋白表达和预后之间的关系，包括死亡、神经发育障碍(NDI)、支气管肺发育不良(BPD)、脑室出血(IVH)、早产儿视网膜病变(ROP)、脑性瘫痪(CP)、念珠菌阳性培养、听力障碍和双眼失明。这些目标将通过以下方式实现：(1)测试遗传相关性，以确定一个基因中影响细胞因子蛋白表达水平或与肺结核相关结果相关的变异；(2)使用定量性状基因座(QTL)分析，寻找与细胞因子蛋白表达水平或与肺结核相关结果相关的QTL；(3)通过具有时间依赖协变量(TDC)的COX比例风险(PH)生存模型，阐明23种细胞因子的蛋白水平与肺结核相关结果之间的关系；(4)测试细胞因子与其他新生儿变量之间的交互作用，以确定影响因素；(5)将这些细胞因子结果与基因分型细胞因子结果联系起来。如果成功，将产生从基因到细胞因子再到结果的联系。我们计划这项工作的科学出版物和演示文稿，并在分析结果和额外样本的指导下，对基因、细胞因子和结果叙事进行详细探索，我们将提交NICHD R01申请。

 DESCRIPTION (provided by applicant): Preterm birth (PTB)-related disorders are the leading cause of perinatal morbidity and mortality. Inflammation exhibits a strong association with these disorders; cytokines are markers for inflammation. Several studies have suggested that fetal genotypes may contribute to the inflammatory response at the feto-maternal interface, which may have implications for membrane rupture, spontaneous PTB, and fetal injury. Although associations have been found between maternal genotypes and PTB-related disorders, few studies have examined and identified fetal genotypes that are strongly associated with the morbidities and mortality associated with PTB, and those that have demonstrated modest association require validation/replication. Thus, the primary aims of the proposed investigation are to identify fetal genetic variation associated with higher risk of PTB-related outcomes, and to identify cytokines that explain this association. By identification of high-risk neonates, the proposed analyses will enhance understanding of the pathophysiology and biological mechanisms leading to PTB-associated outcomes and suggest intervention strategies. Using existing data from the Neonatal Research Network (NRN), the proposed plan will involve analyses on 1,030 samples with genome-wide genotype data and protein expression data at five time points for 23 cytokines. The specific aims of this investigation are to (1) delineate relationships between ¿inflammatory cascade¿ genetic markers and their associated cytokine protein expression levels that may be relevant to PTB-related outcomes, and (2) investigate whether any of the ¿genetic markers and¿cytokines studied suggest differential risk of PTB-related outcomes. The results of this study should allow a complete narrative of the associations among cytokine genetic markers, cytokine protein expression and outcomes, including death, neurodevelopmental impairment (NDI), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), cerebral palsy (CP), Candida positive culture, hearing impairment, and bilateral blindness. These goals will be accomplished by (1) testing ¿genetic¿ associations to identify variants in one gene that affect ¿cytokine¿ protein expression levels ¿or are associated with PTB-related outcomes¿; (2) using quantitative trait loci (QTL) analysis to look for QTLs that are associated with cytokine protein expression levels ¿or with PTB-related outcomes¿; (3) elucidating associations between protein levels of 23 cytokines and PTB-related outcomes through Cox Proportional Hazards (PH) survival models with time-dependent covariates (TDC); (4) testing for interaction effects between cytokines and other neonatal variables to identify effect modifiers; and (5) relating these cytokine-outcome results to genotype-cytokine results. If successful, a link from gene to cytokine to outcome will result. We plan scientific publications and presentations from this work, and, guided by the results of the analysis with additional samples to conduct detailed explorations of the gene to cytokine to outcome narrative, we will submit an NICHD R01 application.