Genetic predisposition to bronchopulmonary dysplasia

Abstract

The objective of this study is to review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and to discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. 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 and phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g., adenosine deaminase and 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. 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).

Keywords: Bronchopulmonary Dysplasia; Genomics; Infant, premature; Polymorphism, genetic; genome-wide association study.

Figure 1

Proposed BPD disease network indicating potential disease-modifying genes and environmental factors (which probably account for much of the center effects) that act on the immature lung, leading to intermediate phenotypes of inflammation, fibrosis, apoptosis or proliferation, atelectasis and cystic change. These in turn lead to the pathophenotypes with varying components of inhibited alveolarization, abnormal lung vascular development and pulmonary hypertension, and airway malacia (tracheo- or broncho-malacia). These pathophenotypes in turn result in long-term impairment of lung function, which may also be modified by genetic factors directly.