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。炎症表现出与这些疾病的强烈关联;细胞因子是炎症的标志物。一些研究表明，胎儿基因型可能有助于在胎儿-母体界面的炎症反应，这可能与胎膜破裂，自发性PTB，胎儿损伤。虽然已发现母亲基因型和PTB相关疾病之间的关联，但很少有研究检查并确定与PTB相关的发病率和死亡率密切相关的胎儿基因型，并且那些已证明适度关联的基因型需要验证/复制。因此，所提出的研究的主要目的是确定与PTB相关结果的高风险相关的胎儿遗传变异，并确定解释这种关联的细胞因子。通过识别高危新生儿，拟议的分析将提高对导致PTB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，拟议的计划将涉及分析1，030个样本的全基因组基因型数据和23种细胞因子在5个时间点的蛋白质表达数据。本研究的具体目的是（1）描述炎症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，这些蛋白表达水平可能与PTB相关结局相关，以及（2）研究所研究的任何遗传标志物和细胞因子是否提示PTB相关结局的差异风险。本研究的结果应允许对细胞因子遗传标记物、细胞因子蛋白表达和结局之间的相关性进行完整叙述，包括死亡、神经发育障碍（NDI）、支气管肺发育不良（BPD）、脑室内出血（IVH）、早产儿视网膜病变（ROP）、脑瘫（CP）、念珠菌阳性培养、听力障碍和双侧失明。这些目标将通过以下方式实现：（1）检测遗传关联以鉴定影响细胞因子蛋白表达水平或与PTB相关结果相关的一个基因中的变体;（2）使用数量性状基因座（QTL）分析来寻找与细胞因子蛋白表达水平或与PTB相关结果相关的QTL;（3）通过具有时间依赖性协变量（TDC）的考克斯比例风险（PH）存活模型阐明23种细胞因子的蛋白质水平与PTB相关结果之间的关联;（4）测试细胞因子与其他新生儿变量之间的相互作用效应以鉴定效应修饰物;和（5）将这些细胞因子结果与基因型细胞因子结果相关联。如果成功，将导致从基因到细胞因子到结果的联系。我们计划从这项工作的科学出版物和演示文稿，并在分析结果的指导下，使用额外的样本进行基因到细胞因子到结果叙述的详细探索，我们将提交NICHD R 01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.