Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities. This study included 532 infants born < 30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways. We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose–response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing. Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.

中文翻译：

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严重的新生儿疾病与极早产儿的 DNA 甲基化差异有关

与足月同龄婴儿相比，非常早产的婴儿更容易出现新生儿疾病。与这些发病率相关的 DNA 甲基化 (DNAm) 的变化可能会产生有关受这些发病率影响的过程的新信息。这项研究包括 532 名出生时 < 30 周妊娠的婴儿，他们参与了极早产儿的新生儿神经行为和结果研究。我们使用了新生儿发病率风险评分，它是 NICU 住院期间发病率的附加指数，包括支气管肺发育不良 (BPD)、严重脑损伤、严重新生儿感染和严重早产儿视网膜病变。在 NICU 出院时从口腔细胞收集 DNA，并使用 Illumina MethylationEPIC 测量 DNAm。我们测试了与新生儿发病风险评分相关的差异甲基化，然后测试了差异甲基化区域 (DMR) 和生物通路的过度表达。我们确定了 10 个差异甲基化 CpG（针对 706,278 次测试进行了 α Bonferroni 调整），它们与三个基因间区域以及 HPS4、SRRD、FGFR1OP、TNS3、TMEM266、LRRC3B、ZNF780A 和 TENM2 的新生儿发病风险评分增加相关。这些主要遵循剂量反应模式，对于 8 个 CpG，DNAm 增加与发病率增加相关，而对于 2 个 CpG，风险评分与 DNAm 减少相关。BPD 是差异甲基化的最主要贡献者。我们还确定了七个潜在的 DMR 和参与 Wnt 信号转导的基因的过度表达；然而，这些结果在针对多重检验进行 Bonferroni 调整后并不显着。新生儿 DNAm，在涉及成纤维细胞生长因子活性、细胞侵袭和迁移以及神经信号和发育的基因中，对早产儿的新生儿健康并发症很敏感。我们假设这些表观遗传特征可能代表新生儿健康和发育的综合标记，并且有希望与临床信息相结合以研究儿童发育障碍。