Antioxidant response genes sequence variants and BPD susceptibility in VLBW infants

Abstract

Background Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing anti-oxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very low birth weight (VLBW) infants. Methods Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1 and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data was analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. Results In our cohort (n=659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. Conclusions Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts.

Inhibition of pre-B cell colony-enhancing factor attenuates inflammation induced by hyperoxia in EA.hy926 cells

“…There is increasing evidence to indicate that oxidative stress is one of the most important events in the development of BPD (31,32). It has been reported that oxidative stress plays an important role in endothelial dysfunction and vascular injury (33).…”

Bronchopulmonary Dysplasia

“…In a trial, 26 newborns with birth weight <1250 g were randomized to receive placebo, low-dose, or high-dose rhSOD within 30 min after the fi rst surfactant. SOD levels in serum, tracheal aspirates, and urine significantly increased in the treatment group with respect to the placebo group [ 148 ]. The lung protective effect of the treatment was dose dependent and tracheal aspirates of SOD-treated newborns showed lower levels of markers of acute lung injury such as neutrophil chemotactic activity and albumin concentration.…”

“…However, in the context of overexpression of IL-1β in a bi-transgenic mouse model, MMP-9 played a protective role, and MMP-9 deficiency, on the contrary, further exaggerated perturbation of lung morphogenesis [ 147 ]. Very recently, genetic variants of antioxidant response elements were found to be associated with an increased risk for BPD [ 148 ].…”

Genetic predisposition to bronchopulmonary dysplasia

“…Poggi et al 43 and Giusti et al 44 showed that SNPs in superoxide dismutase (SOD) 2 and SOD3 were associated with BPD risk. Sampath et al 45 genotyped variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes in a cohort of 659 infants, of whom 284 infants had BPD and 135 had severe BPD. The hypomorphic NQO1 SNP (rs1800566) in homozygous state was associated with increased BPD, while NFE2L2 (nuclear factor erythroid-2 related factor-2) SNP (rs6721961) was associated with decreased severe BPD.…”

“…The hypomorphic NQO1 SNP (rs1800566) in homozygous state was associated with increased BPD, while NFE2L2 (nuclear factor erythroid-2 related factor-2) SNP (rs6721961) was associated with decreased severe BPD. 45 The null genotypes of Glutathione S-transferases GSTM1 and GSTT1 have been associated with BPD in the Chinese Han population. 46 …”