Gene Targets for Intraventricular Hemorrhage (IVH)

描述（由申请人提供）：许多研究已经确定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，即发育中的脑生发基质组织出血，被认为是继发于未成熟的生发基质微血管的脑血流量改变和继发于心室周围静脉梗死。在所有极低体重婴儿中，超过12%的婴儿经历3至4年级IVH，其中四分之三的人出现智力迟钝、脑瘫和/或癫痫发作。根据美国人口普查局、NICHD新生儿网络和疾病预防控制中心的数据，美国每年有3600多例新发智力迟钝病例可归因于3 - 4级IVH，这些儿童的终身护理费用超过36亿美元。早产为大脑发育提供了独特的环境；许多因素，如炎症、低血压和低氧血症，导致IVH已被确定。在过去十年中，Gr 3 - 4 IVH的发生率没有变化。直到最近，关于遗传因素是否在Gr -4 - IVH的发病机制中起作用的信息有限。然而，新的数据强烈表明VLBW双胞胎IVH的家族易感性，并且一些研究已经调查了血栓、炎症和血管基因在Gr 3 - 4 IVH发生中的作用。我们假设对于VLBW婴儿，3 - 4级IVH可归因于环境和遗传因素。遗传因素是等位基因和单倍型尚未确定的基因，使VLBW婴儿易患Gr 3 - 4 IVH。这很可能是炎症、血管、氧化和/或凝血途径的一部分。为了实现这些目标，我们将收集1000名出生体重为500 - 1250g的3 - 4级IVH新生儿和1000名颅超声正常且无IVH证据的对照早产儿的DNA。我们的遗传分析将包括分布在整个基因组中的500,000个标记的全基因组关联研究和候选途径基因研究，目标基因编码已知的血管，炎症，氧化和/或凝血途径的蛋白质。为了确定环境因素对3 - 4级IVH的影响，将收集产前、围产期和新生儿的数据；使用多变量分析，将评估遗传和环境因素对IVH易感性的相对贡献。DNA将存储在NINDS DNA库中。

DESCRIPTION (provided by applicant): Numerous studies have identified Grades 3-4 intraventricular hemorrhage (IVH) as a significant cause of adverse outcome for very low birth weight (VLBW) neonates. IVH, or hemorrhage into the germinal matrix tissues of the developing brain, is believed 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 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 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. However, new data 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, we will collect DNA from 1000 neonates of 500 - 1250 g birth weight with Gr 3 - 4 IVH and 1000 matched control preterm infants with normal cranial ultrasounds and no evidence for IVH. Our 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. DNA will be stored in the NINDS DNA Bank.