Gene Targets for Prevention of Intraventricular Hemorrhage

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 playa 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 both candidate gene association studies targeting genes that encode proteins known to subserve vascular, inflammatory, oxidative and/or coagulation pathways and a whole genome SNP association study of 500,000 markers distributed throughout the genome. In order to determine the relative contribution of environmental factors to Gr 3 - 4 IVH, pre-, periand neonatal data will be collected; using multivariate analyses, the relative contribution of genetic, pharmacologic and environmental factors to the susceptibility to IVH will be assessed. This is a multicenter study and University of Kentucky is one of 12 participating sites.