Genetic Variants Associated with Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants

Abstract

Purpose To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants. Methods Preterm infants in the discovery and replication cohorts were phenotyped for ROP severity. Infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and those in the replication cohort were from the University of Iowa. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness and significant epidemiologic variables. SNPs significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis. Results Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, 2 intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P<3.1x10-5) were associated with severe ROP in the discovery cohort. Following meta-analysis of the two cohorts, rs7934165 increased in associated significance with severe ROP (P=2.9 x10-7). Conclusions Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study