Wachman E M, Hayes M J, Shrestha H, Nikita F N U, Nolin A, Hoyo L, Daigle K, Jones H E, Nielsen D A
Department of Pediatrics, Boston Medical Center, Boston, Massachusetts.
Department of Psychology, Graduate School of Biomedical Sciences & Engineering, University of Maine, Orono, Maine.
Genes Brain Behav. 2018 Sep;17(7):e12476. doi: 10.1111/gbb.12476. Epub 2018 Apr 19.
Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure has significant variability of severity. Preliminary studies have suggested that epigenetic variation within the μ-opioid receptor (OPRM1) gene impacts NAS. We aimed to determine if DNA methylation in OPRM1 within opioid-exposed mother-infant dyads is associated with differences in NAS severity in an independent cohort. Full-term opioid-exposed newborns and their mothers (N = 68 pairs) were studied. A DNA sample was obtained and then assessed for level of DNA methylation at 20 CpG sites within the OPRM1 promoter region by next-generation sequencing. Infants were monitored for NAS and treated with replacement opioids according to institutional protocol. The association between DNA methylation level at each CpG site with NAS outcome measures was evaluated using linear and logistic regression models. Higher methylation levels within the infants at the -18 (11.4% vs 4.4%, P = .0001), -14 (46.1% vs 24.0%, P = .002) and +23 (26.3% vs 12.9%, P = .008) CpG sites were associated with higher rates of infant pharmacologic treatment. Higher levels of methylation within the mothers at the -169 (R = 0.43, P = .008), -152 (R = 0.40, P = .002) and +84 (R = 0.44, P = .006) sites were associated point-wise with longer infant length of stay. Maternal associations remained significant point-wise for -169 (β = 0.07, P = .007) and on an experiment-wise level for +84 (β = -0.10, P = .003) using regression models. These results suggest an association of higher levels of OPRM1 methylation at specific CpG sites and increased NAS severity, replicating prior findings. These findings have important implications for personalized treatment regimens for infants at high risk for severe NAS.
因子宫内阿片类药物暴露导致的新生儿戒断综合征（NAS）严重程度存在显著差异。初步研究表明，μ-阿片受体（OPRM1）基因内的表观遗传变异会影响NAS。我们旨在确定在一个独立队列中，阿片类药物暴露的母婴二元组中OPRM1基因的DNA甲基化是否与NAS严重程度的差异相关。对足月阿片类药物暴露的新生儿及其母亲（N = 68对）进行了研究。获取DNA样本，然后通过下一代测序评估OPRM1启动子区域内20个CpG位点的DNA甲基化水平。对婴儿进行NAS监测，并根据机构方案用替代阿片类药物进行治疗。使用线性和逻辑回归模型评估每个CpG位点的DNA甲基化水平与NAS结局指标之间的关联。婴儿在 -18（11.4%对4.4%，P = .0001）、-14（46.1%对24.0%，P = .002）和 +23（26.3%对12.9%，P = .008）CpG位点的甲基化水平较高与婴儿药物治疗率较高相关。母亲在 -169（R = 0.43，P = .008）、-152（R = 0.40，P = .002）和 +84（R = 0.44，P = .006）位点的甲基化水平较高与婴儿住院时间较长逐点相关。使用回归模型，母亲在 -169位点的关联逐点仍然显著（β = 0.07，P = .007），在 +84位点在实验水平上仍然显著（β = -0.
