title: Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants.
abstract: OBJECTIVE
  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 × 10(-5)) 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 = 2.9 × 10(-7)).
  
  
  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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hartnett
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Margaux A
authors.initials: MA
authors.lastname: Morrison
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Silvia
authors.initials: S
authors.lastname: Smith
authors.affiliation: Dean McGee Eye Center, University of Oklahoma, Oklahoma City, Oklahoma, United States.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Yanovitch
authors.affiliation: Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States.
authors.forename: Tarah
authors.initials: T
authors.lastname: Colaizy
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Momany
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States.
authors.forename: John
authors.initials: J
authors.lastname: Dagle
authors.affiliation: Department of Pediatrics, University of Alabama, Birmingham, Alabama, United States.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Carlo
authors.affiliation: Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Erin A S
authors.initials: EA
authors.lastname: Clark
authors.affiliation: Research Triangle Park, Raleigh, North Carolina, United States.
authors.forename: Grier
authors.initials: G
authors.lastname: Page
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Murray
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: DeAngelis
authors.affiliation: Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Cotten
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005865:Gestational Age; D006801:Humans; D015994:Incidence; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D012178:Retinopathy of Prematurity / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D014481:United States / Q000453:epidemiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human; D004247:DNA
keywords: brain-derived neurotrophic factor; extremely low birth weight; genetic associations; neurovascular; retinopathy of prematurity