TOP 67 - Uncovering Genetic Contributions to Intraventricular Hemorrhage in Extremely Premature Infants

Publication Number: 3798.TOP 67

Megan Garcia-Curran, UCSF Benioff Children's Hospital San Francisco, San Francisco, CA, United States; Thaybeth Malave-Mendez, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Rachel Vassar, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Andrew D. Skol, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States; Dara G. Torgerson, University of California, San Francisco, San Francisco, CA, United States; Aaron Hamvas, Lurie Children's Hospital / Northwestern University, Chicago, IL, United States; Divakar S. Mithal, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States

Background: Intraventricular hemorrhage (IVH) is a cause of significant mortality and morbidity in extremely premature infants, with highest risk in the most premature babies. While many post-natal factors have been identified to increase IVH risk (hypoxic-ischemia, cardiovascular instability, severe respiratory disease), the only independent factor that has been shown to reduce IVH is antenatal steroids (ANS). Since the introduction of ANS, the rate of IVH has remained remarkably stable, raising the possibility of a genetic predisposition to IVH.

There is increasing evidence of genetic contributors to prenatal cerebral hemorrhage, most notably COL4A1/2. There is no similar consensus in the post-natal preterm population, where hemorrhage is much more frequent. Preclinical research has shown that IVH stems from the fragility of the microvasculature of the developing germinal matrix, due to rapid angiogenesis and immature structure of the blood-brain barrier. Multiple genetic contributors have been suggested, but no direct relationship has been found.

This study is the first large-scale analysis of infants with IVH using whole exome sequencing, giving an unprecedented level of genetic detail. Genetic targets could lead to the development of more effective preventative treatments, potentially decreasing the risk of severe IVH.

Objective: Identify single genes or gene networks that contribute to the risk of IVH.

Design/Methods: This study builds off data from the Prematurity and Respiratory Outcomes Program (PROP), a prospective cohort of 765 extremely premature infants (23w0d to 28w6d) born in 13 neonatal intensive care units across the United States between July 2011 and October 2013. It is exempt from IRB review.

We identified 381 infants with both exome sequencing and brain imaging (head ultrasound and/or magnetic resonance imaging). There were 102 patients (27%) with IVH (Grade 1: n=45, Grade 2: 22, Grade 3: 20, Grade 4/Periventricular Hemorrhagic Infarction: 15). The breakdown of patients by gestational age is shown in Figure 1. A candidate list of 175 genes has been identified, including genes involved in cell structure, angiogenesis, cerebral blood flow regulation, and coagulation.

We are performing association testing of candidate genes comparing patients with and without IVH, analysing both common and rare variants using logistic regression, with aggregate variant analyses across all genes using the optimized sequence kernel association test (SKAT-O). Pathway enrichment and gene network analyses will also be performed and all work will be completed by January.

Figure 1: Patients included in the study by gestational age cohorts
(Cohort 1: 23w0d - 24w6d, Cohort 3: 25w0d-25w6d, Cohort 4: 27w0d - 27w6d, Cohort 5: 28w0d - 28w6d)