Dataset Information

Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity.

ABSTRACT: PURPOSE: Retinopathy of prematurity (ROP) is a complex disease with a genetic predisposition, but little is known about its genetic background. It has a clinical resemblance to familial exudative vitreoretinopathy (FEVR), a hereditary disease characterized by defects in the development of retinal vessels. Several studies have suggested that mutations in the causative genes for FEVR may account for a proportion of advanced ROP, but conflicting data have also been reported for some variants. To address the possibility of genetic involvement of FEVR genes in ROP, we performed comprehensive sequence analyses of 53 Japanese patients with advanced ROP for the FEVR-causing genes. METHODS: Peripheral blood DNA was obtained from 53 patients referred to our hospitals for retinal surgery. Polymerase chain reaction followed by direct sequencing of the coding regions of the known FEVR-causing genes (FZD4, LRP5, TSPAN12, and NDP) and a noncoding exon of the NDP gene was performed. Possible pathogenicity of the sequence changes were analyzed by orthologous protein sequence alignment and by computational predictions. RESULTS: We identified six different nonsynonymous DNA variants in the coding region of either the FZD4 gene (p.H69Y, p.R127H, and p.Y211H) or the LRP5 gene (p.R1219H, p.H1383P, and p.T1540M) in seven patients. The corresponding codons of these changes were highly conserved among species, and these changes were predicted to be pathogenic by at least two of four computational prediction programs. No such changes were found in the TSPAN12 and NDP genes. CONCLUSIONS: Six possibly pathogenic variants of FZD4 or LRP5 were found in seven advanced ROP patients. Although these variants do not yet provide definitive evidence that they are causal, the results imply a role of the FZD4 and LRP5 genes in the development of advanced ROP.

SUBMITTER: Kondo H

PROVIDER: S-EPMC3580992 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity.

Kondo Hiroyuki H Kusaka Shunji S Yoshinaga Aki A Uchio Eiichi E Tawara Akihiko A Tahira Tomoko T

Molecular vision 20130225

<h4>Purpose</h4>Retinopathy of prematurity (ROP) is a complex disease with a genetic predisposition, but little is known about its genetic background. It has a clinical resemblance to familial exudative vitreoretinopathy (FEVR), a hereditary disease characterized by defects in the development of retinal vessels. Several studies have suggested that mutations in the causative genes for FEVR may account for a proportion of advanced ROP, but conflicting data have also been reported for some variants ...[more]

PMID: 23441120

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Project description: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 × 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.

Dataset Information

Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity.

Publications

Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity.

Similar Datasets

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