Association of Fetal Genotypes with Cytokine Levels and Preterm Birth

胎儿基因型与细胞因子水平和早产的关联

• 批准号: 8931014
• 负责人: ROBERT F CLARK
• 金额: $ 8.66万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8931014
• 关键词: Affect; African American; American; Bilateral; Biological; Blindness; Bronchopulmonary Dysplasia; Candida; Cerebral Palsy; Cessation of life; Clinical; Collaborations; Cox Proportional Hazards Models; Data; Data Set; Diagnostic; Disease; Environment; Ethnic Origin; European; Exhibits; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Variation; Genotype; Goals; Health; Immune System and Related Disorders; Individual; Infant; Inflammation; Inflammatory; Inflammatory Response; Influentials; Injury; Intervention; Investigation; Iowa; Knowledge; Lead; Link; Mediating; Membrane; Modeling; Morbidity - disease rate; Multicenter Neonatal Research Network; National Institute of Child Health and Human Development; Neonatal; Neurodevelopmental Impairment; Outcome; Pathway interactions; Perinatal; Phenotype; Play; Premature Birth; Prevention; Proportional Hazards Models; Proteins; Publications; Quantitative Trait Loci; Race; Reporting; Research Personnel; Residual state; Retinopathy of Prematurity; Risk; Role; Sampling; Single Nucleotide Polymorphism; Spontaneous Rupture; Survival Analysis; Testing; Time; Validation; Variant; Work; adverse outcome; cytokine; fetal; genetic analysis; genetic association; genome wide association study; genome-wide; hazard; hearing impairment; high risk; improved; inflammatory marker; interest; intraventricular hemorrhage; mortality; neonate; protein expression

 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.

 描述（适用提供）：早产（PTB）相关疾病是围产期发病率和死亡率的主要原因。炎症与这些疾病表现出很强的联系。细胞因子是炎症的标志物。几项研究表明，胎儿基因型可能有助于胎儿界面的炎症反应，这可能对膜破裂，赞助PTB和胎儿损伤有影响。尽管在母体基因型和与PTB相关的疾病之间发现了关联，但很少有研究检查和鉴定出与与PTB相关的病态和死亡率密切相关的胎儿基因型，以及那些证明了适度的关联验证/复制的胎儿基因型。这是拟议投资的主要目的是确定与较高的与PTB相关结果的风险相关的胎儿遗传变异，以及 确定解释这种关联的细胞因子。通过鉴定高风险新生儿，提出的分析将增强对导致PTB相关结果的病理生理学和生物学机制的理解，并提出干预策略。使用来自新生儿研究网络（NRN）的现有数据，该计划将涉及对23个细胞因子的五个时间点的1,030个样品进行1,030个样本，这些样本具有全基因组基因型数据和蛋白质表达数据。这项投资的具体目的是（1）在可能与PTB相关结果相关的炎症级联层之间的关系及其相关的细胞因子蛋白表达水平之间，以及（2）研究遗传标记物和细胞因子是否暗示了与PTB相关的PTB相关风险的不同风险。 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文化，听力障碍和双侧失明。这些目标将通过（1）测试遗传学的关联来实现，以鉴定一个影响»细胞因子蛋白表达水平的基因中的变体或与PTB相关的结果相关的； （2）使用定量性状区域（QTL）分析来寻找与细胞因子蛋白表达水平�或与PTB相关的结果相关的QTL； （3）通过COX比例危害（PH）生存模型与时间依赖性协变量（TDC）之间的23种细胞因子和与PTB相关结果之间的蛋白质水平之间的关联； （4）测试细胞因子和其他新生儿变量之间的相互作用效应以识别效应修饰剂； （5）将这些细胞因子成分结果与基因型 - 循环因子结果有关。如果成功，将会导致从基因到细胞因子与结局的链接。我们计划了这项工作的科学出版物和演讲，并在分析结果的指导下，并提供了其他样本，以对细胞因子进行详细的探索，以进行结果叙事，我们将提交NICHD R01应用。