From the, Department of Psychiatry and Behavioral Sciences, Addiction Sciences Division, Medical University of South Carolina, Charleston, South Carolina, USA.
Alcohol Clin Exp Res. 2020 Oct;44(10):2084-2096. doi: 10.1111/acer.14431. Epub 2020 Sep 19.
While the opiate antagonist, naltrexone, is approved for treating alcohol use disorder (AUD), not everyone who receives the medication benefits from it. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-O-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response.
Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1 genotype (75 G-allele carriers and 77 A-allele homozygotes) and also genotyped for DAT1 VNTR (9 vs. 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes.
Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p = 0.021, d = 0.72) or COMT val/val genotypes (p = 0.05, d = 0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p = 0.09, d = 0.70) or COMT met carriers (p = 0.03, d = 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers.
These results suggest that individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.
尽管阿片类拮抗剂纳曲酮已被批准用于治疗酒精使用障碍（AUD），但并非每个接受该药物治疗的患者都能从中受益。本研究旨在评估 OPRM1 SNP rs1799971 是否与多巴胺转运体基因 DAT1/SLC6A3 VNTR rs28363170 或儿茶酚-O-甲基转移酶（COMT）基因 SNP rs4680 相互作用，从而预测纳曲酮的反应。
符合 DSM-IV 酒精依赖标准的个体根据 OPRM1 基因型（75 G 等位基因携带者和 77 A 等位基因纯合子）以及 DAT1 VNTR（9 与 10 重复）或 COMT SNP（val/val 与 met 携带者）进行随机分组，分别接受纳曲酮（50mg/d）或安慰剂治疗。在 16 周和治疗结束时评估大量饮酒天数（%HDD）。根据基因型计算纳曲酮反应的效应大小（d）。
与安慰剂相比，纳曲酮显著降低了 OPRM1 G 携带者中 DAT1 10/10（p=0.021，d=0.72）或 COMT val/val 基因型（p=0.05，d=0.80）的%HDD，而 OPRM1 A 纯合子中 DAT1 9 重复携带者（p=0.09，d=0.70）或 COMT met 携带者（p=0.03，d=0.63）的反应程度较轻。其他所有基因型组合对纳曲酮均无差异反应。腹泻/腹痛在 OPRM1 A 纯合子中更为突出，这些个体也是 DAT1 9 或 COMT met 携带者。
这些结果表明，具有更阿片类药物反应性基因型（OPRM1 G 携带者）的 AUD 个体，如果具有表明正常/较低多巴胺水平的基因型（DAT1 10/10 或 COMT val/val），则对纳曲酮的反应更好，而具有较低阿片类药物反应性基因型（OPRM1 A 纯合子）的个体，如果具有表明较高多巴胺水平的基因型（DAT1 9 重复或 COMT met 携带者），则对纳曲酮的反应更好。这些结果可能导致更个性化的 AUD 治疗。
