Variability of Response to Methadone: Genome-Wide DNA Methylation Analysis in Two Independent Cohorts

Marie-Claire, Cynthia; Crettol, Séverine; Cagnard, Nicolas; Bloch, Vanessa; Mouly, Stéphane; Laplanche, Jean‐Louis; Bellivier, Frank; Lépine, Jean‐Pierre; Eap, Chin B.; Vorspan, Florence

doi:10.2217/epi.15.110

Cited by 17 publications

(9 citation statements)

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“…To the best of our knowledge, there is only one previous report of the potential modulation of LRP1B in human addiction. A decrease in the DNA methylation of the LRP1B promoter was found in blood cells from patients stabilized at high daily methadone doses compared with patients stabilized at low doses 52 . Interestingly, in that previously published sample 53 , a high methadone dose was significantly associated with lifetime cocaine dependence.…”

Section: Discussionmentioning

confidence: 86%

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

et al. 2020

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Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (N = 40), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, Lrp1b, was differentially expressed in both regions. In patients, LRP1B was significantly associated with both CIS and CIH. CIH was also associated with VPS13A, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The LRP1B minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected p = 0.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta = −0.965 and −2.35 for heterozygotes and homozygotes, respectively, p < 0.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that LRP1B and VPS13A are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.

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Section: Discussionmentioning

confidence: 86%

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

et al. 2020

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“…Work in humans generally relies on postmortem tissue from long-term drug users, and studies have found significant epigenetic differences in the brains of former addicts compared to non-addicts [21,22]. While the brain is the most relevant tissue in terms of neuroadaptation and drug-seeking behavior, epigenetic markers of addiction have also been detected in peripheral tissues such as the blood and sperm [23][24][25][26][27][28]. Easily accessible peripheral tissues are clearly the practical choice when it comes to defining biomarkers of drug use and/or predictors of individual risk for addiction.…”

Section: Introductionmentioning

confidence: 99%

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter

et al. 2020

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Background: A long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here, we examine whether we can detect DNA methylation changes associated with a few days' use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics. Results: The perioperative methylome underwent significant changes over the three visits that were primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the OPRM1 promoter. There was a significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5-210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: < 25 MME, 25-90 MME, and ≥ 90 MME. Using mixed-effects modeling, 4 CpGs had significant positive associations with opioid dose at two-tailed p value < 0.05, and overall, 9 of the 10 OPRM1 promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, one-tailed p value = 0.02) and duration of opioid use (regression coefficient = 0.003, one-tailed p value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RASrelated signaling gene, RASL10A, that may be predictive of opioid dosage. Conclusion: The present study provides evidence that the hypermethylation of the OPRM1 promoter is in response to opioid use and that epigenetic differences in OPRM1 and other sites are associated with a short-term use of therapeutic opioids.

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“…Work in humans generally relies on postmortem tissue from long-term drug users, and studies have found significant epigenetic differences in the brain of former addicts compared to non-addicts [21, 22]. While the brain is the most relevant tissue in terms of neuroadaptation and drug seeking behavior, epigenetic marks of addiction have also been detected in peripheral tissues such as blood and sperm [23–28]. Easily accessible peripheral tissues are clearly the practical choice when it comes to defining biomarkers of drug use and/or predictors of individual risk for addiction.…”

Section: Introductionmentioning

confidence: 99%

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter

Sandoval-Sierra

iacutea

Brooks

et al. 2020

Preprint

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BackgroundLong-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here we examine whether we can detect DNA methylation changes associated with few days use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics.ResultsThe perioperative methylome underwent significant changes over the three visits that was primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the OPRM1 promoter. There was significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5–210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: <25 MME, 25–90 MME, ≥90 MME. Using mixed effects modeling, 4 CpGs had significant positive associations with opioid dose at 2-tailed p-value < 0.05, and overall, 9 of the 10 OPRM1 promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, 1-tailed p-value = 0.02), and duration of opioid use (regression coefficient = 0.003, 1-tailed p-value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RAS-related signaling gene, RASL10A, that may be predictive of opioid dosage.ConclusionThe present study provides evidence that the hypermethylation of the OPRM1 promoter is in response to opioid use, and that epigenetic differences in OPRM1 and other sites are associated with short-term use of therapeutic opioids.

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Variability of Response to Methadone: Genome-Wide DNA Methylation Analysis in Two Independent Cohorts

Abstract: Our results indicate that differentially methylated sites are associated with methadone daily dose and give insights into the molecular pathways underlying this interindividual dose variability.

Cited by 17 publications

References 63 publications

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter

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