Gene Targets for Intraventricular Hemorrhage (IVH)

描述(由申请人提供)：许多研究已经确定3-4级脑室出血(IVH)是极低出生体重(VLBW)新生儿不良结局的重要原因。IVH，或发育中脑生发基质组织的出血，被认为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%的极低出生体重婴儿经历了3-4级IVH，其中四分之三发展为智力低下、脑瘫和/或癫痫。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，美国每年有超过3600例新发的可归因于Gr 3-4 IVH的智力低下病例，这些儿童一生的护理费用超过36亿美元。早产代表着大脑发育的独特环境；许多因素，如炎症、低血压和低氧血症，都被确定为导致IVH。Gr3-4型IVH的发病率在过去十年中没有变化。直到最近，关于遗传因素是否在Gr3-4 IVH的发病机制中发挥作用的信息有限。然而，新的数据有力地表明了VLBW双胞胎对IVH的家族易感性，一些研究已经探讨了血栓形成、炎症和血管基因在Gr3-4 IVH发生中的作用。我们推测，对于极低出生体重的婴儿，Gr3-4 IVH既与环境因素有关，也与遗传因素有关。遗传因素是尚未确定的基因的等位基因和单倍型，使极低出生体重儿易患Gr 3-4 IVH。其中许多很可能是炎症、血管、氧化和/或凝血途径的一部分。为了实现这些目标，我们将从1000名出生体重500-1250g的IVH新生儿和1000名匹配的对照组早产儿中收集DNA，这些早产儿的头颅超声正常，但没有IVH的证据。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，以及针对编码为血管、炎症、氧化和/或凝血途径已知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Gr3-4 IVH的贡献，将收集产前、围产期和新生儿的数据；利用多变量分析，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.