Genetic Risk Factors of Bronchopulmonary Dysplasia

Abstract

ABSTRACT:The aim of the study was to assess the association between bronchopulmonary dysplasia (BPD) and polymorphisms of genes coding for vascular endothelial growth factor (VEGF), transforming growth factor (TGF-␤1), insulin-like growth factor (IGF-1), and 5,10-methylenetetrahydrofolate reductase (MTHFR). A sample of 181 newborns with mean gestational age of 28 wk was prospectively evaluated. Molecular analysis of TGF-␤1 Ϫ800GϾA, Ϫ509CϾT, 10TϾC, 25GϾC, VEGF Ϫ460TϾC and 405GϾC and MTHFR 677CϾT polymorphisms were performed and the number of CA repeats in the promoter region of IGF-1 gene was assessed. The frequency of all TGF-␤1, IGF-1, and MTHFR polymorphisms, as well as the frequency of VEGF 405GϾC polymorphism was similar in all groups. The newborns with Ϫ460TT and Ϫ460CT genotypes were significantly overrepresented in the BPD groups compared with the no BPD group. Multivariate analysis revealed that carrying T allele increased the risk of BPD by 9% (95%CI: 2-14%) above the baseline risk established for given gestational age, length of oxygen therapy, and sex. Based on our data from a single center, we propose that VEGF Ϫ460TϾC polymorphism may influence the risk of BPD. A n increase in survival of extremely preterm infants has been associated with an increased incidence of bronchopulmonary dysplasia (BPD) (1), which has become a major clinical challenge because of its serious health consequences. Surviving infants with BPD are at higher risk for recurrent respiratory infections, bronchial hyperreactivity, repeated hospitalizations, and neurodevelopmental abnormalities (1,2).The current consensus is that BPD is a complex disease: the interaction of a susceptible host with a multitude of external risk factors underlies its pathogenesis. It is still unclear why BPD progresses to severe disease in one group of very low birth weight (VLBW) infants but regresses spontaneously in other infants with similar clinical characteristics. This difference in BPD development may result from differences in reactions to inflammatory stimuli and varied ability to tolerate oxidative stress and inflammation. Genetic foundations for the development of BPD are implicated in twin studies, which reveal highly significant concordance rates for BPD: 3.69-fold in monozygotic and 1.4-fold in dizygotic twins (3).The criteria for selection of BPD candidate genes in the present study were their potential involvement in angiogenesis and alveolarization regulating mechanisms, as well as their involvement in free radical elimination.The first factor worth examining is vascular endothelial growth factor (VEGF). VEGF is a relatively specific endothelial cell mitogen that regulates endothelial cell differentiation and angiogenesis, and plays a central role in vascular repair. VEGF has multiple roles in vascular development and maintenance and is essential for the formation of embryonic vasculature (4,5). The absence of VEGF results in impaired fetal lung microvascular development. The VEGF gene is also a good candidate because there are a consid...

A Polymorphism in the Macrophage Migration Inhibitory Factor Promoter Is Associated With Bronchopulmonary Dysplasia

“…Interestingly, a recent report showed that a promoter polymorphism (Ϫ460 T/C) of the VEGF gene was associated with an increased risk of BPD, independently from the duration of O 2 exposure (12). Given the fact that MIF has been shown to promote angiogenesis (19,20) and to induce VEGF production in the neonatal mouse lung (23), and that both genes are HIF-inducible, it is tempting to speculate that polymorphisms of the MIF and VEGF genes may affect the same maturational pathway in neonatal lung.…”

Definition and Outpatient Management of the Very Low-Birth-Weight Infant With Bronchopulmonary Dysplasia

“…The human lung undergoes maturation during five stages, each of which has distinct growth milestones at specific gestational periods [9]. The latter two stages extend from 26-28 to 32-36 weeks gestation [7,[12][13][14][15].…”

Chorioamnionitis, Postnatal Factors and Proinflammatory Response in the Pathogenetic Sequence of Bronchopulmonary Dysplasia

“…A recent animal study demonstrated that hypoxia had a substantial effect on LPS-induced pulmonary inflammation by increasing the magnitude of lung injury reflected by increased expression of inflammatory mediators, excessive neutrophil accumulation and increased vascular permeability [40] . The role of a genetic predisposition to BPD is currently under investigation but has not provided conclusive data to date [41][42][43] .…”