GENE TARGETS FOR IVH

Baylor College Of Medicine, Houston TX

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Abstract

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.