Sampath Venkatesh, Garland Jeffery S, Helbling Daniel, Dimmock David, Mulrooney Neil P, Simpson Pippa M, Murray Jeffrey C, Dagle John M
Department of Pediatrics, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, Wisconsin.
Department of Pediatrics, Wheaton Franciscan Health Care, Milwaukee, Wisconsin.
Pediatr Res. 2015 Mar;77(3):477-83. doi: 10.1038/pr.2014.200. Epub 2014 Dec 17.
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 antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very-low-birth-weight (VLBW) infants.
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 were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD.
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.
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.
氧化应激导致的肺损伤是支气管肺发育不良（BPD）发病机制的一个因素。核因子红细胞2相关因子2（NFE2L2）通过诱导含有抗氧化反应元件（ARE）的酶来调节细胞对氧化应激的保护反应。我们假设ARE基因变异会调节极低出生体重（VLBW）婴儿患BPD的易感性或严重程度。
从VLBW婴儿采集的血样用于对超氧化物歧化酶2（SOD2）、NFE2L2、谷氨酸半胱氨酸连接酶催化亚基（GCLC）、谷胱甘肽S-转移酶P1（GSTP1）、血红素加氧酶1（HMOX1）和醌氧化还原酶1（NQO1）基因的变异进行基因分型。利用TaqMan探针（应用生物系统公司（ABI），纽约州大岛）对单核苷酸多态性（SNP）进行基因分型，并使用ABI HT7900分析数据。测试遗传显性和隐性模型以确定SNP与BPD之间的关联。
在我们的队列（n = 659）中，284名婴儿患有BPD；其中135名发展为重度BPD。纯合状态的低功能NQO1 SNP（rs1800566）与BPD增加相关，而NFE2L2 SNP（rs6721961）与整个队列以及白人婴儿中重度BPD减少相关。在针对流行病学混杂因素进行调整的回归模型中，NQO1和NFE2L2 SNP分别与BPD和重度BPD相关。
NFE2L2 - ARE轴中的基因变异可能导致早产儿中观察到的BPD易感性差异。这些结果需要在独立队列中得到证实。
