Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants

M Elizabeth Hartnett; Margaux A Morrison; Silvia Smith; Tammy L Yanovitch; Terri L Young; Tarah Colaizy; Allison Momany; John Dagle; Waldemar A Carlo; Erin A S Clark; Grier Page; Jeff Murray; Margaret M DeAngelis; C Michael Cotten

doi:10.1167/iovs.14-14841

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Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants

Journal article

Open access

Peer reviewed

Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants

M Elizabeth Hartnett, Margaux A Morrison, Silvia Smith, Tammy L Yanovitch, Terri L Young, Tarah Colaizy, Allison Momany, John Dagle, Waldemar A Carlo, Erin A S Clark, …

Investigative ophthalmology & visual science, Vol.55(10), pp.6194-6203

08/12/2014

DOI: 10.1167/iovs.14-14841

PMCID: PMC4188045

PMID: 25118269

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https://doi.org/10.1167/iovs.14-14841View

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Abstract

To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants. 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. 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)). Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.

Brain-Derived Neurotrophic Factor - genetics

United States - epidemiology

Follow-Up Studies

Humans

Male

Retinopathy of Prematurity - genetics

Incidence

Genetic Variation

Ethnic Groups - genetics

Infant, Premature, Diseases - ethnology

Retinopathy of Prematurity - ethnology

Infant, Premature, Diseases - genetics

Female

Brain-Derived Neurotrophic Factor - metabolism

Retrospective Studies

Infant, Newborn

Infant, Extremely Low Birth Weight

Severity of Illness Index

Risk Factors

Gestational Age

Linkage Disequilibrium

Polymorphism, Genetic

DNA - genetics

Infant, Premature

Infant, Premature, Diseases - metabolism

Retinopathy of Prematurity - metabolism

Details

Title: Subtitle: Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants
Creators: M Elizabeth Hartnett - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States
Margaux A Morrison - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States
Silvia Smith - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States
Tammy L Yanovitch - Dean McGee Eye Center, University of Oklahoma, Oklahoma City, Oklahoma, United States
Terri L Young - Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States
Tarah Colaizy - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States
Allison Momany - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States
John Dagle - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States
Waldemar A Carlo - Department of Pediatrics, University of Alabama, Birmingham, Alabama, United States
Erin A S Clark - Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, United States
Grier Page - Research Triangle Park, Raleigh, North Carolina, United States
Jeff Murray - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States
Margaret M DeAngelis - Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, United States
C Michael Cotten - Duke Eye Center, Duke University Medical Center, Durham, North Carolina, United States Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.55(10), pp.6194-6203
DOI: 10.1167/iovs.14-14841
PMID: 25118269
PMCID: PMC4188045
NLM abbreviation: Invest Ophthalmol Vis Sci
ISSN: 0146-0404
eISSN: 1552-5783
Publisher: United States
Grant note: U10 HD27856 / NICHD NIH HHS UG1 HD040492 / NICHD NIH HHS M01 RR997 / NCRR NIH HHS M01 RR16587 / NCRR NIH HHS 5U10 HD040492-12 / NICHD NIH HHS U10 HD027871 / NICHD NIH HHS M01 RR008084 / NCRR NIH HHS U10 HD27880 / NICHD NIH HHS UL1 RR24979 / NCRR NIH HHS U01 HG4423 / NHGRI NIH HHS M01 RR016587 / NCRR NIH HHS U10 HD040498 / NICHD NIH HHS U10 HD27904 / NICHD NIH HHS U10 HD021373 / NICHD NIH HHS U10 HD040492 / NICHD NIH HHS M01 RR39 / NCRR NIH HHS M01 RR32 / NCRR NIH HHS M01 RR7122 / NCRR NIH HHS U10 HD27853 / NICHD NIH HHS U01 HD36790 / NICHD NIH HHS M01 RR70 / NCRR NIH HHS U10 HD040689 / NICHD NIH HHS U10 HD027904 / NICHD NIH HHS M01 RR8084 / NCRR NIH HHS U10 HD40498 / NICHD NIH HHS U10 HD40492 / NICHD NIH HHS M01 RR007122 / NCRR NIH HHS U10 HD021385 / NICHD NIH HHS U10 HD040461 / NICHD NIH HHS UL1 RR024979 / NCRR NIH HHS R01 EY015130 / NEI NIH HHS M01 RR80 / NCRR NIH HHS U10 HD34216 / NICHD NIH HHS U10 HD27851 / NICHD NIH HHS U01 HG004423 / NHGRI NIH HHS M01 RR006022 / NCRR NIH HHS U10 HD53109 / NICHD NIH HHS U10 HD21397 / NICHD NIH HHS U10 HD021397 / NICHD NIH HHS U10 HD21415 / NICHD NIH HHS U10 HD21364 / NICHD NIH HHS K23 HD061910 / NICHD NIH HHS U10 HD053109 / NICHD NIH HHS U10 HD027856 / NICHD NIH HHS U10 HD27871 / NICHD NIH HHS U10 HD027880 / NICHD NIH HHS U10 HD027853 / NICHD NIH HHS U10 HD021364 / NICHD NIH HHS U10 HD40689 / NICHD NIH HHS U10 HD027851 / NICHD NIH HHS U10 HD21385 / NICHD NIH HHS U10 HD40461 / NICHD NIH HHS M01 RR633 / NCRR NIH HHS M01 RR750 / NCRR NIH HHS U10 HD034216 / NICHD NIH HHS M01 RR6022 / NCRR NIH HHS U01 HD036790 / NICHD NIH HHS U10 HD21373 / NICHD NIH HHS U10 HD27881 / NICHD NIH HHS R01EY015130 / NEI NIH HHS M01 RR30 / NCRR NIH HHS
Language: English
Date published: 08/12/2014
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Pediatric Dentistry; Craniofacial Anomalies Research Center; Biochemistry and Molecular Biology; Dental Research; Neonatology
Record Identifier: 9984024512302771

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