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首页> 外文期刊>Pharmacogenomics and Personalized Medicine >DNA methylation at the mu-1 opioid receptor gene (OPRM1) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion
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DNA methylation at the mu-1 opioid receptor gene (OPRM1) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion

机译：mu-1阿片受体基因（ OPRM1 ）启动子处的DNA甲基化可预测脊柱融合后的术前，急性和慢性术后疼痛

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Introduction: The perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene ( OPRM1 ) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP). Methods: A prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2–3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2–3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant ( P <0.05) nongenetic variables. Results: Majority (83%) of the patients reported no pain preoperatively, while CPSP occurred in 36% of the subjects (44/121). Regression on dichotomized preoperative pain outcome showed association with methylation at six CpG sites (1, 3, 4, 9, 11, and 17) ( P <0.05). Methylation at CpG sites 4, 17, and 18 was associated with higher AUC after adjusting for opioid consumption and preoperative pain score ( P <0.05). After adjusting for postoperative opioid consumption and preoperative pain score, methylation at CpG sites 13 and 22 was associated with CPSP ( P <0.05). Discussion: Novel CPSP biomarkers were identified in an active regulatory region of the OPRM1 gene that binds multiple transcription factors. Inhibition of binding by DNA methylation potentially decreases the OPRM1 gene expression, leading to a decreased response to endogenous and exogenous opioids, and an increased pain experience.
机译：简介：围手术期疼痛经历显示出巨大的个体差异，并且难以预测。已知mu-1阿片类受体基因（OPRM1）在阿片类疼痛途径中起重要作用。由于脱氧核糖核酸（DNA）甲基化是基因表达的有效阻遏物，因此在OPRM1启动子上评估了DNA甲基化，作为术前，急性和慢性术后疼痛（CPSP）的预测因子。方法：在标准方案下，对接受特发性脊柱侧弯的133名青少年进行脊柱融合的前瞻性观察队列研究。在手术前后和术后2-3个月收集有关疼痛，阿片类药物消耗，焦虑和灾难性的数据（使用经过验证的问卷）。评估的结果为术前疼痛，急性术后疼痛（超过48小时的疼痛评分曲线下面积[AUC]）和CPSP（术后2-3个月的数字评分量表> 3/10）。术前收集的血样通过在OPRM1基因启动子上的22个CpG位点进行焦磷酸测序来分析DNA甲基化。使用多变量回归评估每个疼痛结局与每个CpG位点甲基化百分比的关联，并调整显着（P <0.05）的非遗传变量。结果：绝大多数（83％）的患者术前未见疼痛，而CPSP的发生率为36％（44/121）。二分法术前疼痛结果的回归显示与六个CpG位点（1、3、4、9、11和17）的甲基化相关（P <0.05）。调整阿片类药物的摄入量和术前疼痛评分后，CpG位点4、17和18处的甲基化与较高的AUC相关（P <0.05）。调整术后阿片类药物的摄入量和术前疼痛评分后，CpG 13位和22位的甲基化与CPSP相关（P <0.05）。讨论：在与多个转录因子结合的OPRM1基因的活性调节区中鉴定出了新型CPSP生物标记。 DNA甲基化抑制结合可能会降低OPRM1基因的表达，从而导致对内源性和外源性阿片类药物的反应减少，并增加疼痛体验。

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