Epigenetic Variation in the Mu-Opioid Receptor Gene in Infants with Neonatal Abstinence Syndrome

Abstract

Objective 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 and correlate them with NAS outcomes. Study design DNA samples from cord blood or saliva were analyzed for 86 infants 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 co-variates and multiple genetic testing. Results 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 versus non-treated infants [adjusted difference δ=3.2% (95% CI 0.3–6.0%), p=0.03; NS after multiple testing correction]. There was hypermethylation at the −14 [δ=4.9% (95% CI 1.8–8.1%), p=0.003], −10 [δ=5.0% (95% CI 2.3–7.7%), p=0.0005)], and +84 [δ=3.5% (95% CI 0.6 – 6.4), p=0.02] CpG sites in infants requiring ≥2 medications which remained significant for −14 and −10 after multiple testing correction. Conclusions Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing.

DNA methylation at the mu-1 opioid receptor gene (<em>OPRM1</em>) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion

“…Similarly, seven CpG sites showed significant hypermethylation of blood DNA taken from male opioid addicts when compared to blood DNA from controls (CpGs 5, 9, 10, 11, 18, and 23) 26. Increased methylation within the OPRM1 promoter (at −14, −10 [sites 10, 11]) was also found to be associated with worse neonatal abstinence syndrome outcomes in infants exposed to opioids in utero 42. It has been shown in mouse brain tissues that DNA methylation of the OPRM1 promoter decreases expression of the gene; through interaction with chromatin-remodeling factors, remodeling occurs, thus allowing access for Sp1 binding,43 which results in the MOR upregulation.…”

“…However, this approach has been employed successfully before 25,26,42. Fan and Zhang compared methylation profiles of human chromosome 6 ( OPRM1 gene location), derived from 12 tissues, and reported that CpG island methylation profiles were highly correlated between somatic tissues 57.…”

Gender Considerations in Addiction: Implications for Treatment

“…Specifically, variants in the OPRM1 and COMT genes were associated with shorter hospital stays and less need for treatment among infants with NAS (85). In addition, hypermethylation within the OPRM1 promoter was associated with worse NAS outcomes (86). …”

Opioid Replacement for Pregnant Mothers With Opioid Use Disorder and Fetal Neurodevelopment: A Review

“…A group of investigators showed similar higher levels of methylation on the OPMR1 promoter in the saliva and blood of infants with neonatal abstinence syndrome. However, the study could not determine whether the epigenetic change was a pre-existing risk factor or a change caused by the opioid exposure itself [21].…”