BACKGROUND Second hand smoke (SHS) exposure is associated with pediatric asthma, and oxidative stress is believed to play a role in mediating this association. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is important for the defense against oxidative stress. OBJECTIVE To explore interactions between NFE2L2 genotype and SHS exposure in pediatric asthma risk. METHODS We used a genotyped subset of patients of European ancestry (N=669, median age at enrollment=6.8 years) enrolled in the clinical cohort Greater Cincinnati Pediatric Clinic Repository as the study population, and a population-based pediatric cohort (N=791) to replicate our findings. History of asthma diagnosis was obtained from medical records, and SHS exposure was obtained from questionnaires. Four NFE2L2 tagging SNPs were included in the analysis, and interactions between SHS and NFE2L2 genotype were evaluated using logistic regression. RESULTS Three of the analyzed SNPs, rs10183914, rs1806649, and rs2886161, interacted significantly with SHS exposure to increase asthma risk (p≤0.02). The interaction was replicated in an independent cohort for rs10183914 (p=0.04). Interactions between SHS exposure and NFE2L2 genotype were also associated with an increased risk of hospitalization (p=0.016). In stratified analyses, NFE2L2 genotype was associated with daily asthma symptoms in children with SHS exposure (OR=3.1; p=0.048). No association was found in children without SHS exposure. Examination of publicly available chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets confirmed the presence of active histone marks and binding sites for particular transcription factors overlapping the coordinates for the significantly associated SNPs. CONCLUSIONS & CLINICAL RELEVANCE Our study provides evidence that NFE2L2 genotype interacts with SHS exposure to affect both asthma risk and severity in children and identifies a population of children at increased risk of asthma development.

中文翻译：

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二手烟和 NFE2L2 基因型相互作用增加了儿童哮喘的风险和严重程度

背景 二手烟 (SHS) 暴露与儿童哮喘有关，据信氧化应激在介导这种关联中发挥作用。核因子（红细胞衍生2）样2（NFE2L2）对于防御氧化应激很重要。目的探讨 NFE2L2 基因型与 SHS 暴露在儿童哮喘风险中的相互作用。方法 我们使用在临床队列大辛辛那提儿科诊所资料库中登记的欧洲血统患者的基因分型子集（N=669，入组时的中位年龄=6.8 岁）作为研究人群，以及基于人群的儿科队列（N=791 ) 来复制我们的发现。从病历中获得哮喘诊断史，从问卷中获得 SHS 暴露。分析中包括四个 NFE2L2 标记 SNP，使用逻辑回归评估 SHS 和 NFE2L2 基因型之间的相互作用。结果 分析的三个 SNP，rs10183914、rs1806649 和 rs2886161，与 SHS 暴露显着相互作用以增加哮喘风险 (p≤0.02)。交互作用在 rs10183914 的独立队列中被复制 (p=0.04)。SHS 暴露和 NFE2L2 基因型之间的相互作用也与住院风险增加有关（p=0.016）。在分层分析中，NFE2L2 基因型与 SHS 暴露儿童的日常哮喘症状相关（OR=3.1；p=0.048）。在未接触 SHS 的儿童中未发现相关性。对公开可用的染色质免疫沉淀和测序 (ChIP-seq) 数据集的检查证实，存在与显着相关 SNP 坐标重叠的特定转录因子的活性组蛋白标记和结合位点。结论和临床相关性 我们的研究提供了 NFE2L2 基因型与 SHS 暴露相互作用以影响儿童哮喘风险和严重程度的证据，并确定了哮喘发展风险增加的儿童群体。