Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain.
Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain.
Neonatology. 2022;119(5):575-584. doi: 10.1159/000525305. Epub 2022 Jun 27.
The oxygen load provided to preterm infants during postnatal stabilization caused significant modifications of DNA methylation in the preterm epigenome. We aimed to assess if there was an association between DNA methylation changes and neurodevelopmental outcomes.
Preterm infants were followed until 2 years after birth. Dried blood spots were processed, and DNA methylation was measured using the MassARRAY technology of Sequenom. We selected specific genes that corresponded to differentially methylated CpG sites that correlated with the oxygen load at 2 h after birth. Neurodevelopmental outcome was blindly assessed using Bayley-III scale.
Of 32 eligible patients, we completed the methylation analysis in 19 patients and the neurodevelopmental evaluation in 22. Comparison of differential methylation analysis between time 0 (cord blood) and 2 h after birth showed 74 significant CpGs, out of which 14 correlated with the oxygen load received at birth. Out of these 14 genes, only TRAPPC9 showed statistically significant differences at 2 years of age between the infants who received >500 mL versus <500 mL O2/kg. Premature who received >500 mL O2/kg showed significantly lower motor composite scores.
DISCUSSION/CONCLUSIONS: Premature who received higher oxygen load scored lower motor composite scores and showed a hypermethylation pattern of TRAPPC9 at 2 years of age. TRAPPC9 mutations are associated with neurodevelopmental delay and intellectual disability, so changes in the CpG methylation of this gene and its subsequent expression alteration can produce a similar phenotype. Further studies with a greater sample size are needed to confirm these findings.
在出生后稳定化期间，早产儿接受的氧气负荷导致早产儿表观基因组中的 DNA 甲基化发生显著改变。我们旨在评估 DNA 甲基化变化与神经发育结局之间是否存在关联。
对早产儿进行随访，直到出生后 2 年。处理干燥血斑，并使用 Sequenom 的 MassARRAY 技术测量 DNA 甲基化。我们选择了与出生后 2 小时的氧气负荷相关的差异甲基化 CpG 位点对应的特定基因。使用贝利-III 量表对神经发育结局进行盲法评估。
在 32 名符合条件的患者中，我们完成了 19 名患者的甲基化分析和 22 名患者的神经发育评估。对出生时（脐血）和出生后 2 小时之间的差异甲基化分析进行比较，显示出 74 个显著的 CpG，其中 14 个与出生时接受的氧气负荷相关。在这 14 个基因中，只有 TRAPPC9 在接受 >500 mL 与 <500 mL O2/kg 的婴儿之间在 2 岁时显示出统计学上的显著差异。接受 >500 mL O2/kg 的早产儿的运动综合评分明显较低。
讨论/结论：接受更高氧气负荷的早产儿的运动综合评分较低，并且在 2 岁时显示出 TRAPPC9 的高甲基化模式。TRAPPC9 突变与神经发育迟缓有关，智力障碍，因此该基因的 CpG 甲基化变化及其随后的表达改变可能产生类似的表型。需要更大样本量的进一步研究来证实这些发现。
