Integrated Genomic Analyses in Bronchopulmonary Dysplasia - 25/02/15
, C. Michael Cotten, MD 2, Grier P. Page, PhD 3, Waldemar A. Carlo, MD 1, Jeffrey C. Murray, MD 4, Soumyaroop Bhattacharya, MS, MEd 5, Thomas J. Mariani, PhD 5, Alain C. Cuna, MD 6, Ona M. Faye-Petersen, MD 7, David Kelly, MD 7, Rosemary D. Higgins, MD 8on behalf of the
Genomics and Cytokine Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network∗
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.
Le texte complet de cet article est disponible en PDF.Keyword : ADARB2, BPD, FDR, GWAS, SNP
Plan
| Supported by the National Institutes of Health (General Clinical Research Center M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 RR24979) and the Eunice Kennedy Shriver NICHD (U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, U10 HD53109). J.M. received assistance for the GENEVA study from the National Human Genome Research Institute (U01 HG4423). Data collected at participating sites of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were transmitted to RTI International, the data coordinating center for the network, which stored, managed, and analyzed the data for this study. The authors declare no conflicts of interest. |
Vol 166 - N° 3
P. 531 - mars 2015 Retour au numéro
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