Abstract
The μ-opioid receptor is the site of action of opiates and opioids. We examined whether there are differences in cytosine:guanine (CpG) dinucleotide methylation in the OPRM1 promoter between former heroin addicts and controls. We analyzed methylation at 16 CpG dinucleotides in DNA obtained from lymphocytes of 194 Caucasian former severe heroin addicts stabilized in methadone maintenance treatment and 135 Caucasian control subjects. Direct sequencing of bisulfite-treated DNA showed that the percent methylation at two CpG sites was significantly associated with heroin addiction. The level of methylation at the −18 CpG site was 25.4% in the stabilized methadone-maintained former heroin addicts and 21.4% in controls (p=0.0035, generalized estimating equations (GEE); p=0.0077, t-test; false discovery rate (FDR)=0.048), and the level of methylation at the +84 CpG dinucleotide site was 7.4% in cases and 5.6% in controls (p=0.0095, GEE; p=0.0067, t-test; FDR=0.080). Both the −18 and the +84 CpG sites are located in potential Sp1 transcription factor-binding sites. Methylation of these CpG sites may lead to reduced OPRM1 expression in the lymphocytes of these former heroin addicts.
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Acknowledgements
We thank E Ducat, B Ray, D Melia, L Borg, K Bell, P McHugh, J Schluger, and H Hofflich for recruiting, screening, and assessment of study subjects, and M Randesi for sequencing assistance. We also thank CD Allis for his helpful advice before the start of this project and in the review of this paper, to M Rouault for assistance, and to O Levran for critical review of this paper. This study was supported by National Institutes of Health (NIH) grants R03-DA022266 (DN), K05-DA000049 (MJK), P60-DA005130 (MJK), R01-MH79880 (MJK), RR UL1RR024143 (BC), NIH-MH R01-44292 (JO), and NSFC grants 30730057 and 30700442 from the Chinese Government (JO).
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All the authors, except JO, declare that, except for the income received from our primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interests. One author, JO, declares that he personally receives book royalties from the Johns Hopkins University Press and that his laboratory receives funding from Hoffmann-La Roche Inc.
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Nielsen, D., Yuferov, V., Hamon, S. et al. Increased OPRM1 DNA Methylation in Lymphocytes of Methadone-Maintained Former Heroin Addicts. Neuropsychopharmacol 34, 867–873 (2009). https://doi.org/10.1038/npp.2008.108
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DOI: https://doi.org/10.1038/npp.2008.108
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