Exome sequencing and pathway analysis for identification of genetic variability relevant for bronchopulmonary dysplasia (BPD) in preterm newborns: A pilot study

Carrera, Paola; Resta, Chiara Di; Volonteri, Chiara; Castiglioni, Emanuela; Bonfiglio, Silvia; Lazarevic, Dejan; Cittaro, Davide; Stupka, Elia; Ferrari, Maurizio; Somaschini, Marco; R, Magaldi; Rinaldi, Matteo; Maffei, G; Stronati, Mauro; Tzialla, Chryssoula; Borghesi, A.; Tagliabue, Paolo; Fedeli, Tiziana; Citterio, Marco; Mosca, Fabio; Colnaghi, Mariarosa; Lavizzari, Anna; Agosti, Massimo; Francescato, Gaia; Pomero, Giulia; Dalmazzo, Cristina; Boldrini, Antonio; Scaramuzzo, Rosa Teresa; Bertino, Enrico; Borgione, Silvia Maria; Martano, C; Carnielli, Virgilio P.; Nobile, Stefano; Auriemma, A.; Bellan, Cristina; Carrera, G; Zambetti, Chiara; Pucello, Riccardo; Palatta, Sara

doi:10.1016/j.cca.2015.01.001

Cited by 52 publications

(29 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Novel mis-sense mutations in ATP-binding cassette 3 (ABCA3) gene were also found in 3 patients, suggesting that ABCA3 may require further investigation in BPD. 62 This pilot study is encouraging, as it suggests that NGS techniques may help investigate the genetic background of BPD. Studies of this type identify multiple potential candidate genes that will require additional functional studies as well as genetic analysis to determine their relevance and importance to lung development and pathogenesis of BPD.…”

Section: Identification Of the Genetic Basis Of Bpdmentioning

confidence: 81%

“…Carrera et al 62 performed whole exome sequencing on 26 Italian infants of Caucasian origin with severe BPD, selected from a larger prospective cohort of 366 premature infants from 12 NICUs. Overall, 3369 novel variants were identified (1524 potentially damaging), with a median of 400 variations per sample (100 with a strong impact on protein structure and function).…”

Section: Identification Of the Genetic Basis Of Bpdmentioning

confidence: 99%

See 1 more Smart Citation

Genetic predisposition to bronchopulmonary dysplasia

Lal

Ambalavanan

2015

Seminars in Perinatology

View full text Add to dashboard Cite

Objective To review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. Findings Genetic factors contribute much of the variance in risk for BPD. Studies to date evaluating single or a few candidate genes have not been successful in yielding results that are replicated in GWAS, perhaps due to more stringent p-value thresholds. GWAS studies have identified only a single gene (SPOCK2) at genome-wide significance in a European White and African cohort, which was not replicated in two North American studies. Pathway gene set analysis in a North American cohort confirmed involvement of known pathways of lung development and repair (e.g. CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g. adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD. The genetic basis of severe BPD is different from that of mild/moderate BPD, and the variants/pathways associated with BPD vary by race/ethnicity. A pilot study of whole exome sequencing identified hundreds of genes of interest, and indicated the overall feasibility as well as complexity of this approach. Conclusion Better phenotyping of BPD by severity and pathophysiology, and careful analysis of race/ethnicity is required to gain a better understanding of the genetic basis of BPD. Future translational studies are required for the identification of potential genetic predispositions (rare variants and dysregulated pathways) by next generation sequencing methods in individual infants (personalized genomics).

show abstract

Section: Identification Of the Genetic Basis Of Bpdmentioning

confidence: 81%

Section: Identification Of the Genetic Basis Of Bpdmentioning

confidence: 99%

Genetic predisposition to bronchopulmonary dysplasia

Lal

Ambalavanan

2015

Seminars in Perinatology

View full text Add to dashboard Cite

show abstract

“…BPD is a multifactorial disease characterized by impaired alveolar and vascular development (17). Therapy with hyperoxia is often used to treat newborns with respiratory disorders; however, high concentrations and extended durations of oxygen exposure in a newborn may lead to oxidative stress injury and lung epithelial cell death in the immature lung, which is crucial in the development of BPD (18,19).…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin attenuates hyperoxia-induced lung injury by upregulating epidermal growth factor-like domain 7 in newborn rats

Cui

Chen

et al. 2016

Biomedical Reports

View full text Add to dashboard Cite

The aim of the present study was to observe the effects of recombinant human erythropoietin (rhEPO) on the expression of epidermal growth factor-like domain 7 (EGFL7) and cell apoptosis in lung tissue following hyperoxic lung injury in newborn rats. The 96 Sprague-Dawley newborn rats were randomly divided into 4 groups (n=24) as follows: Room air-exposed control group, room air-exposed rhEPO-treated group, hyperoxia-exposed group and the hyperoxia-exposed rhEPO-treated group. Pups (n=8) from each group were sacrificed on postnatal days 3, 7 and 14. The pulmonary morphometric and microvessel density changes were observed. In addition, the mRNA and protein expression levels of EGFL7, B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) in lung tissue samples were measured. The rats in the hyperoxia-exposed group exhibited alveolar and pulmonary vascular dysplasia, as well as low mRNA and protein expression levels of EGFL7 and Bcl-2, in addition to high level of Bax in the lung tissue samples when compared with the room air-exposed control group (P<0.05). However, in the hyperoxia-exposed rhEPO-treated group the lung histopathology was improved, and the protein and mRNA expression levels of EGFL7 and Bcl-2 were increased compared with the hyperoxia-exposed group (P<0.05). Furthermore, the expression level of Bax was lower than that of the hyperoxia-exposed group (P<0.05). The present study demonstrated that rhEPO promotes alveolar development and increases pulmonary vascular density by upregulating the expression level of EGFL7 in hyperoxia-induced lung injury of newborn rats.

show abstract

“…Another pilot study in Italy sequenced the exomes of 26 unrelated patients with severe BPD and analyzed potentially detrimental variants [34]. Their results reinforced the role of rare mutations in BPD susceptibility.…”

Section: Exome Sequencing Of Bronchopulmonary Dysplasia Patients and mentioning

confidence: 96%

The genetic predisposition to bronchopulmonary dysplasia

Snyder

et al. 2016

Current Opinion in Pediatrics

View full text Add to dashboard Cite

Purpose of review Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants. Twin studies have shown strong heritability underlying this disease; however, the genetic architecture of BPD remains unclear. Recent findings A number of studies employed different approaches to characterize the genetic aberrations associated with BPD, including candidate gene studies, genome-wide association studies, exome sequencing, integrative omics analysis, and pathway analysis. Candidate gene studies identified a number of genes potentially involved with the development of BPD, but the etiological contribution from each gene is not substantial. Copy number variation studies and three independent genome-wide association studies did not identify genetic variations significantly and consistently associated with BPD. A recent exome-sequencing study pointed to rare variants implicated in the disease. In this review, we summarize these studies’ methodology and findings, and suggest future research directions to better understand the genetic underpinnings of this potentially life-long lung disease. Summary Genetic factors play a significant role in the development of BPD. Recent studies suggested that rare variants in genes participating in lung development pathways could contribute to BPD susceptibility.

show abstract

Exome sequencing and pathway analysis for identification of genetic variability relevant for bronchopulmonary dysplasia (BPD) in preterm newborns: A pilot study

Cited by 52 publications

References 56 publications

Genetic predisposition to bronchopulmonary dysplasia

Genetic predisposition to bronchopulmonary dysplasia

Erythropoietin attenuates hyperoxia-induced lung injury by upregulating epidermal growth factor-like domain 7 in newborn rats

The genetic predisposition to bronchopulmonary dysplasia

Contact Info

Product

Resources

About