Wachman Elisha M, Hayes Marie J, Lester Barry M, Terrin Norma, Brown Mark S, Nielsen David A, Davis Jonathan M
Pediatrics, Boston Medical Center, Boston, MA.
Psychology, Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME.
J Pediatr. 2014 Sep;165(3):472-8. doi: 10.1016/j.jpeds.2014.05.040. Epub 2014 Jul 1.
Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants with NAS outcomes.
DNA samples from cord blood or saliva were analyzed for 86 infants who were being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with ≥ 2 medications, and length of hospital stay. We adjusted for covariates and multiple genetic testing.
Sixty-five percent of infants required treatment for NAS, and 24% required ≥ 2 medications. Hypermethylation of the OPRM1 promoter was measured at the -10 CpG in treated vs nontreated infants (adjusted difference δ = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the -14 (δ = 4.9% [95% CI, 1.8%-8.1%], P = .003), -10 (δ = 5.0% [95% CI, 2.3-7.7%], P = .0005), and +84 (δ = 3.5% [95% CI, 0.6-6.4], P = .02) CpG sites in infants requiring ≥ 2 medications, which remained significant for -14 and -10 after multiple testing correction.
Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing.
因子宫内接触阿片类药物导致的新生儿戒断综合征（NAS）具有高度变异性，遗传因素似乎起着重要作用。药物接触后可发生胞嘧啶：鸟嘌呤（CpG）二核苷酸甲基化的表观遗传变化，这可能有助于解释NAS的变异性。我们将阿片类药物暴露婴儿的μ-阿片受体（OPRM1）启动子中的DNA甲基化水平与NAS结局进行了关联分析。
根据机构方案，对86例接受NAS治疗的婴儿的脐带血或唾液DNA样本进行分析。测定了16个OPRM1 CpG位点的甲基化水平，并将其与NAS结局指标相关联，包括治疗需求、使用≥2种药物治疗以及住院时间。我们对协变量和多重基因检测进行了校正。
65%的婴儿需要接受NAS治疗，24%的婴儿需要使用≥2种药物。在接受治疗与未接受治疗的婴儿中，OPRM1启动子在-10 CpG处检测到高甲基化（校正差异δ=3.2%[95%CI，0.3-6.0%]，P=.03；多重检验校正后无统计学意义）。在需要使用≥2种药物的婴儿中，-14（δ=4.9%[95%CI，1.8%-8.1%]，P=.003）、-10（δ=5.0%[95%CI，2.3-7.7%]，P=.0005）和+84（δ=3.5%[95%CI，0.6-6.4]，P=.02）CpG位点存在高甲基化，多重检验校正后-14和-10位点仍具有统计学意义。
OPRM1启动子内甲基化增加与更差的NAS结局相关，这与基因沉默一致。
