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

Abstract

Citation: Hartnett ME, Morrison MA, Smith S, et al. Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants. Invest Ophthalmol Vis Sci. 2014;55:6194-6203. DOI: 10.1167/iovs.14-14841 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 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. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. 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. Single nucleotide polymorphisms 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. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 3 10 À5 ) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P ¼ 2.9 3 10 À7 ).CONCLUSIONS. Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.

Advances in diagnosis, clinical care, research, and treatment in retinopathy of prematurity

“…A US multicenter study from the Neonatal Research Network studied approximately 1,000 infants born with birth weight <1,000 g (extremely low birthweight) and found variants in intronic regions of the gene encoding BDNF associated with severe ROP. 13 Other studies have also found associations with factors within the WNT signaling pathway, including FZD4 , associated with growth impairment and ROP. 14 These findings support the line of thinking that neurovascular connections play a role in the development with ROP.…”

Advances in understanding and management of retinopathy of prematurity

“…(163) Using genetically tested blood spots from infants in the same cohort, variants in the intronic region of the gene BDNF were found in association with severe ROP in extremely low birth weight infants. (74)…”

“…(56) Genetic variants in VEGF, EPAS1 (both associated with hypoxia regulation) in members of the WNT signaling pathway (important in development and the disease familial exudative vitreoretinopathy (FEVR))(46, 96) and SOD (encodes superoxide dismutase, an antioxidant enzyme) have been reported in association with any ROP. (74) Members of the WNT pathway have been most commonly found in association with severe ROP. Known mutations of FEVR were associated with intrauterine growth restriction and severe ROP in preterm infants of older gestational ages, suggesting that the presence of FEVR mutations increases the risk of preterm birth and severe ROP in infants who would not have been predicted to develop severe ROP based on degree of prematurity.…”

“…Known mutations of FEVR were associated with intrauterine growth restriction and severe ROP in preterm infants of older gestational ages, suggesting that the presence of FEVR mutations increases the risk of preterm birth and severe ROP in infants who would not have been predicted to develop severe ROP based on degree of prematurity. (41) In a large candidate gene study of blood from 1000 extremely low birth weight infants enrolled in the Neonatal Research Network, intronic variants in the gene that encodes brain-derived neurotrophic factor (BDNF) were highly associated with severe ROP compared to either no ROP or non-severe ROP, (68, 74) supporting a link between vascular and neural pathways in extreme prematurity and ROP.…”

Retinopathy of prematurity: the need for prevention

“…Several very small studies have found genetic variants in EPAS1, VEGF, SOD, and members of the WNT family in association with ROP. However, a larger study (817 infants and 543 infants in a replication cohort) to determine genetic variants associated with the severe ROP in a candidate gene cohort study of US preterm infants using the whole genome amplified DNA from the stored blood spot samples and the analyses such as, controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables in both cohorts, showed that only two intronic single-nucleotide polymorphism in the gene BDNF were associated with the severe ROP 85,86…”