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Multicenter Study
. 2015 Mar;166(3):531-7.e13.
doi: 10.1016/j.jpeds.2014.09.052. Epub 2014 Nov 6.

Integrated genomic analyses in bronchopulmonary dysplasia

Namasivayam Ambalavanan  1 , C Michael Cotten  2 , Grier P Page  3 , Waldemar A Carlo  4 , Jeffrey C Murray  5 , Soumyaroop Bhattacharya  6 , Thomas J Mariani  6 , Alain C Cuna  7 , Ona M Faye-Petersen  8 , David Kelly  8 , Rosemary D Higgins  9 ; Genomics and Cytokine Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
Collaborators, Affiliations
Multicenter Study

Integrated genomic analyses in bronchopulmonary dysplasia

Namasivayam Ambalavanan et al. J Pediatr. 2015 Mar.

Abstract

Objective: To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors.

Study design: A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models.

Results: Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD.

Conclusions: Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pathways at FDR<0.1. Venn diagram indicating number of pathways significant at FDR<0.1 and overlap for outcomes of BPD/death, severe BPD/death, and severe BPD in survivors.
Figure 2
Figure 2
Evaluation of miR-219 and CD44 in a newborn mouse model (Panels A-D) and in human lung (Panels E-F). Lung miR-219 (Panel A) and CD44 mRNA (Panel B) decreased during alveolar septation, with expression on postnatal days 14 and 42 significantly less as compared with day 1; *p<0.05. Lung miR-219 (Panel C) and CD44 mRNA (Panel D) were also increased on postnatal day 14 during hyperoxia exposure (*p<0.05 compared with air). Lung miR-219 (Panel E) and CD44 mRNA (Panel F) were increased in human lungs with BPD as compared to early preterm or term stillbirth lungs (Mean±SEM; n=4/group)
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