GENE TARGETS FOR IVH

IVH 的基因靶标

• 批准号: 7950649
• 负责人: HEIDI Eigenrauch KARPEN
• 金额: $ 0.28万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950649
• 关键词: Alleles; Antihypertensive Agents; Biology; Birth Weight; Blood Vessels; Brain; Caring; Censuses; Centers for Disease Control and Prevention (U.S.); Cephalic; Cerebral Palsy; Cerebrovascular Circulation; Child; Chronic lung disease; Clinical Research; Coagulation Process; Computer Retrieval of Information on Scientific Projects Database; DNA; Data; Enrollment; Environment; Environmental Risk Factor; Event; Funding; Gender; Gene Targeting; Genes; Genetic; Genome; Grant; Haplotypes; Hemorrhage; Human Genome; Hypotension; Hypoxemia; Incidence; Indomethacin; Infant; Infarction; Inflammation; Inflammatory; Injury; Institution; Linkage Disequilibrium; Low Birth Weight Infant; Medicine; Mental Retardation; Molecular Profiling; Multivariate Analysis; Mutation; National Institute of Child Health and Human Development; Neonatal; Outcome; Pathogenesis; Pathway interactions; Perinatal; Play; Predisposition; Premature Birth; Premature Infant; Proteins; Randomized; Relative (related person); Research; Research Personnel; Resources; Role; Secondary to; Seizures; Site; Source; Steroid therapy; Study Subject; Susceptibility Gene; Thrombophilia; Tissues; Twin Multiple Birth; Ultrasonography; United States National Institutes of Health; Variant; Venous; base; college; cost; experience; genetic analysis; genome wide association study; intraventricular hemorrhage; neonate; postnatal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Numerous studies have identified Grades 3-4 intraventricular hemorrhage (IVH) as a significant cause of adverse outcome for very low birthweight (VLBW) neonates. IVH, or hemorrhage into the germinal matrix tissues of the developing brain, is believed to be secondary to changes in cerebral blood flow to the immature germinal matrix microvasculature and secondary periventricular venous infarction. Over 12% of all VLBW infants experience Gr. 3-4 IVH, and three quarters of these develop mental retardation, cerebral palsy and/or seizures. Based on data from the U.S. Census Bureau, the NICHD Neonatal Network and the CDC, there are over 3600 new cases of mental retardation attributable to Gr. 3-4 IVH in the U.S. each year, and the lifetime care costs for these children exceed 3.6 billion dollars. Preterm birth represents a unique environment for the developing brain; many factors such as inflammation, hypotension and hypoxemia that contribute to IVH have been identified. The incidence of Gr. 3-4 IVH has not changed, however, over the past ten years. Until recently, there has been limited information on whether genetic factors play a role in the pathogenesis of Gr. 3-4 IVH. New data, however, strongly suggest familial susceptibility for IVH in VLBW twins, and several studies have investigated the role of thrombophilia, inflammatory and vascular genes in the genesis of Gr. 3-4 IVH. We hypothesize that for VLBW infants, Gr. 3-4 IVH is attributable to both environmental and genetic factors. The genetic factors are alleles and haplotypes of as yet unidentified genes that render VLBW infants susceptible to Gr. 3-4 IVH. It is likely that many are part of inflammatory, vascular, oxidative and/or coagulation pathways. To accomplish these aims, this randomized, multi-center study, in aggregate, will collect DNA from 1000 neonates of 500-1250g birthweight with Gr. 3-4 IVH and 1000 matched control preterm infants with normal cranial ultrasounds and no evidence for IVH. The genetic analyses will include a whole genome association study of 500,000 markers distributed throughout the genome and candidate pathway gene studies targeting genes that encode proteins known to subserve vascular, inflammatory, oxidative and/or coagulation pathways. In order to determine the contribution of environmental factors to Gr. 3-4 IVH, pre-, peri- and neo-natal data will be collected; using multivariate analyses, the relative contribution of genetic and environmental factors to the susceptibility to IVH will be assessed. This is an NIH funded, randomized multi-center trial, of which Baylor College of Medicine is one of 14 participating institutions. The total number of study infants will be 1000 with Grade 3 or 4 IVH and 1000 matched controls. Enrollment will take place over the first four years of the study. Our site plans to enroll at total of 248 infants (124 with Gr 3 or 4 IVH and 124 matched controls) over the four year grant period. I. HYPOTHESES: 1. For preterm neonates, IVH is attributable to a combination of environmental and genetic factors. 2. The genetic factors are alleles and haplotypes of as yet unidentified genes that render VLBW infants susceptible to IVH when born at 500 - 1250 g. 3. Many of these as yet unidentified genes are part of vascular, inflammatory, oxidative and/or coagulation pathways. II. SPECIFIC AIMS: 1. In order to assess the relative contribution of genetic factors to IVH in VLBW preterm neonates, we will perform a whole genome SNP association (WGA) study of 500,000 markers distributed throughout the human genome on two groups of infants: 1000 neonates born weighing 500 - 1250 grams who have experienced Grade 3 - 4 IVH and 1000 matched (i.e., gender, birth weight and site) control infants with normal cranial ultrasounds and no evidence for IVH. IVH will be assessed by cranial ultrasound at 7 - 10 and 21 - 28 postnatal days. This aim will permit us to identify alleles and haplotypes associated with Gr 3 - 4 IVH in VLBW preterm infants. 2. We will identify functional variants within intervals associated with Gr 3 - 4 IVH following the WGA (whole genome association). The results of WGA will identify intervals showing linkage disequilibrium with Gr 3 - 4 IVH. We will then proceed to identify underlying functional variants. Within intervals implicated in the WGA, genes will be prioritized based on their expression profiles and previous biology implicating them in injury to developing brain. Determination of complete haplotypes and re-sequencing of prioritized genes in these intervals will be performed. This will identify the alleles and haplotypes showing strongest linkage disequilibrium with Gr 3 - 4 IVH. In addition, complete re-sequencing of prioritized genes can identify independent deleterious mutations, which will strengthen evidence that a susceptibility gene has been identified. 3. In order to assess the relative contribution of environmental factors to Gr 3 - 4 IVH in VLBW preterm neonates, pre-, peri- and neonatal data will be collected on all study subjects; these will include hypotensive events, postnatal steroid therapy, ante- and postnatal Indomethacin exposure, chronic lung disease and other environmental factors unique to preterm birth. 4. Using multivariate analyses, the relative contribution of genetic, pharmacologic and environmental susceptibility factors to Gr 3 - 4 IVH will be assessed.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 许多研究已确定 3-4 级脑室内出血 (IVH) 是极低出生体重 (VLBW) 新生儿不良结局的重要原因。 IVH，即发育中大脑的生发基质组织出血，被认为是继发于未成熟生发基质微血管的脑血流变化和继发性脑室周围静脉梗塞。超过 12% 的 VLBW 婴儿患有 Gr. 3-4 例脑室内出血，其中四分之三出现智力低下、脑瘫和/或癫痫发作。 根据美国人口普查局、NICHD 新生儿网络和 CDC 的数据，有超过 3600 例新的精神发育迟滞病例可归因于 Gr.美国每年发生3-4起IVH，这些孩子的终生护理费用超过36亿美元。早产为大脑发育提供了独特的环境；已经确定了导致 IVH 的许多因素，例如炎症、低血压和低氧血症。 Gr 的发病率。然而，3-4 IVH 在过去十年中没有改变。直到最近，关于遗传因素是否在 Gr. 的发病机制中发挥作用的信息还很有限。 3-4 脑室内出血。然而，新数据强烈表明极低出生体重双胞胎对 IVH 具有家族易感性，并且多项研究调查了血栓形成倾向、炎症和血管基因在 Gr. 的发生中的作用。 3-4 脑室内出血。我们假设对于 VLBW 婴儿，Gr. 3-4 IVH 可归因于环境和遗传因素。遗传因素是尚未鉴定的基因的等位基因和单倍型，这些基因使 VLBW 婴儿容易感染 Gr。 3-4 脑室内出血。许多可能是炎症、血管、氧化和/或凝血途径的一部分。为了实现这些目标，这 随机、多中心研究总共将从 1000 名出生体重 500-1250 克的新生儿中收集 DNA。 3-4 IVH 和 1000 名匹配的对照早产儿，其颅骨超声检查正常，但没有 IVH 证据。遗传分析将包括对分布在整个基因组中的 500,000 个标记进行的全基因组关联研究，以及针对编码已知促进血管、炎症、氧化和/或凝血途径的蛋白质的基因的候选途径基因研究。为了确定环境因素对 Gr 的贡献。 3-4 将收集 IVH、产前、围产期和新生儿数据；使用多变量分析，将评估遗传和环境因素对 IVH 易感性的相对影响。这是一项 NIH 资助的随机多中心试验，贝勒医学院是 14 个参与机构之一。研究的婴儿总数为 1000 名患有 3 级或 4 级 IVH 的婴儿和 1000 名匹配的对照婴儿。注册将在研究​​的前四年进行。 我们的网站计划在四年资助期内总共招募 248 名婴儿（124 名患有 3 级或 4 级 IVH 的婴儿和 124 名匹配的对照婴儿）。 I. 假设： 1. 对于早产儿，IVH 是环境和遗传因素共同作用的结果。 2. 遗传因素是尚未鉴定的基因的等位基因和单倍型，使极低出生体重婴儿在出生体重为500 - 1250 g时易患IVH。 3. 其中许多尚未鉴定的基因是血管、炎症、氧化和/或凝血途径的一部分。 二.具体目标： 1. 为了评估遗传因素对 VLBW 早产新生儿 IVH 的相对影响，我们将对两组婴儿进行全基因组 SNP 关联 (WGA) 研究，研究分布在整个人类基因组中的 500,000 个标记：1000 名出生体重 500 - 1250 克、经历过 3 - 4 级 IVH 的新生儿和 1000 名匹配的（即性别、出生）新生儿。体重和部位）对照正常婴儿 颅骨超声检查，没有 IVH 的证据。 IVH 将在出生后 7 - 10 和 21 - 28 天通过颅脑超声进行评估。 这一目标将使我们能够鉴定与 VLBW 早产儿 3-4 IVH 相关的等位基因和单倍型。 2. 我们将根据 WGA（全基因组关联）识别与 Gr 3 - 4 IVH 相关的区间内的功能变异。 WGA 的结果将确定显示与 Gr 3 - 4 IVH 连锁不平衡的区间。然后我们将继续识别潜在的功能变体。在 WGA 涉及的时间间隔内，基因将根据其表达谱和先前的生物学（表明它们对发育中的大脑造成损伤）进行优先排序。将在这些时间间隔内确定完整的单倍型并重新测序优先基因。这将鉴定与 Gr 3 - 4 IVH 显示最强连锁不平衡的等位基因和单倍型。此外，对优先基因的完整重测序可以识别独立的有害突变，这将加强已识别出易感基因的证据。 3. 为了评估环境因素对 VLBW 早产儿 3-4 组 IVH 的相对影响，将收集所有研究对象的产前、围产期和新生儿数据；这些包括低血压事件、产后类固醇治疗、产前和产后吲哚美辛暴露、慢性肺病和早产特有的其他环境因素。 4. 使用多变量分析，将评估遗传、药理学和环境易感因素对 3-4 级 IVH 的相对贡献。