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Progress in understanding the genetics of bronchopulmonary dysplasia

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Abstract

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infants. Its treatment imposes considerable healthcare burden and costs in the perinatal and early childhood period and patients are usually left with lifelong deficits in lung function. Evidence exists for different pathophysiologic pathways that can promote the structural changes that characterize BPD, including the impairment in alveolarization; however, there is increasing interest regarding heritable factors that may predispose very low birth weight infants to BPD. Our review focuses on recent publications that have investigated genetic factors that may potentially contribute to such reported heritability. These publications point us toward some possible genomic candidates for further study, but certainly do not identify any particular gene or gene pathway that would be inferred to be contributing substantially to the underlying etiology of BPD.

Introduction

Bronchopulmonary dysplasia (BPD) remains a leading cause of morbidity and mortality in premature infants1 and the risk of developing BPD rises with decreasing gestational age (GA) and birth weight (BW).2., 3. Although much research has been conducted to discover pathophysiologic mechanisms responsible for BPD,2 and there is evidence for specific mediators and pathways,3 there has been little progress in decreasing the incidence of BPD in very low birth weight infants (VLBW) who have a BW < 1500 g. As discussed in further detail later, twin studies4., 5., 6. have suggested that genetic factors are the major risk for developing BPD. Accordingly, investigators have used a variety of strategies to identify the heritable factors. With the exception of previous twin studies, our review focuses on research that has been published from 2006 onwards. We refer the readers to a previous review7 for earlier work (e.g.,8).

Section snippets

Approaches to discover heritable factors

In reviewing the extant literature on genetic factors influencing the risk of human BPD, one finds reference to a variety of approaches, including studies involving familial aggregation, twins, candidate genes, and genome-wide association (GWA) studies. A brief description of each of these approaches is provided below.

Familial aggregation

During the era of Northway's old BPD, Nickerson et al.12 evaluated premature infants with respiratory distress syndrome (RDS), some of whom developed BPD and some who did not develop BPD. They reported an increased incidence of BPD in patients with a family history of asthma, a disorder that is known to have familial aggregation.

Twin studies

Parker et al.4 evaluated BPD, defined as supplemental oxygen at 28 days PNA, in twins having BW < 1500 g and demonstrated if the first twin had BPD the odds ratio was 20.9 in unadjusted and 12.3 in adjusted analyses for the second twin to have BPD. Although this suggested that genetic factors were present, since the investigators did not determine zygosity, they could not attempt to exclude the role of shared environmental risk factors. Indeed, the analyses by “same-sex” of the twin pair did not

SPOCK2

Hadchouel et al.20 studied 418 Caucasian–French and African–French premature infants who were born <28 weeks GA in 3 centers in France from 2002–2009. Ethnicity was determined by the geographic origin of each parent. BPD was diagnosed using “physiologic test” to assess the need for supplemental oxygen at 36 weeks PMA21; there was a 22% incidence of BPD. The authors first did a GWA study on some of the patients (43 BPD and 162 controls) but used “pooled DNA” for each of the case and control

Candidate genes, TAG SNPs, and haplotypes

Several decades of research have identified potential pathophysiologic pathways or molecules that may be responsible for the acute and chronic characteristics of BPD. Accordingly, investigators have evaluated whether specific alterations in the sequence of candidate genes, as illustrated by SNPs, might be associated with a change in the risk of developing BPD. Further, we discuss different recent publications. For further details regarding the relevance of these genes to potential

Summary

The literature published from 2006 onwards shares many characteristics. Studies in general have been small in sample size with nearly all studies including fewer than 100 moderate/severe BPD patients. The criteria defining BPD, and the groupings for mild, moderate and severe BPD, have been somewhat variable across studies. A surprising number of studies have compared BPD infants to late term or term infants and in some cases even to adults. Associations that are observed in such studies could

Acknowledgment

Supported by the NIH/NHLBI (RC2 HL101748) with supplemental funding from the March of Dimes Prematurity Center at Stanford.

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