Genome-wide association study identifies a potent locus associated with human opioid sensitivity.
Genome-wide association study identifies a potent locus associated with human opioid sensitivity.
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DOI：
10.1038/mp.2012.164
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发表时间：
2014-01
影响因子：
11
通讯作者：
Ikeda, K.
中科院分区：
文献类型：
--
作者：
Nishizawa, D.;Fukuda, K.;Kasai, S.;Hasegawa, J.;Aoki, Y.;Nishi, A.;Saita, N.;Koukita, Y.;Nagashima, M.;Katoh, R.;Satoh, Y.;Tagami, M.;Higuchi, S.;Ujike, H.;Ozaki, N.;Inada, T.;Iwata, N.;Sora, I.;Iyo, M.;Kondo, N.;Won, M-J;Naruse, N.;Uehara-Aoyama, K.;Itokawa, M.;Koga, M.;Arinami, T.;Kaneko, Y.;Hayashida, M.;Ikeda, K.
阿片类药物，如吗啡和芬太尼，被广泛用作治疗急性和慢性疼痛的有效镇痛药。此外，阿片系统在吗啡、乙醇、可卡因和其他各种药物的奖赏效应中起着关键作用。尽管众所周知，阿片类药物敏感性在个体受试者之间存在很大差异，但迄今为止报告的几种候选遗传多态性不足以充分了解人类阿片类药物敏感性的广泛个体间差异。通过在健康受试者中进行多阶段全基因组关联研究（GWAS），我们发现跨越2q33.3- 2 q34的连锁不平衡块内的遗传多态性与疼痛的整容手术后对术后阿片类镇痛药的需求密切相关。最佳候选单核苷酸多态性（SNP）rs 2952768的C等位基因与更多的镇痛需求相关，在接受腹部手术的患者中获得了一致的结果。此外，该SNP中C等位基因的携带者在甲基苯丙胺依赖、酒精依赖和饮食失调患者中表现出对严重药物依赖的脆弱性较低，并且在健康受试者的人格问卷中表现出较低的“奖励依赖”得分。此外，该SNP的C/C基因型与邻近基因CREB 1的表达升高显著相关。这些结果表明，该基因座中的SNP是迄今为止已知的与人类阿片类药物敏感性相关的最有效的遗传因素，影响阿片类镇痛药的疗效和对严重物质依赖的易感性。我们的研究结果为疼痛和药物依赖的个性化治疗提供了有价值的信息。
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3–2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower ‘Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
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DOI：
10.1038/nrg2544
发表时间：
2009-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Ioannidis JP;Thomas G;Daly MJ
通讯作者：
Daly MJ
DOI：
10.1073/pnas.172091899
发表时间：
2002-08-20
影响因子：
11.1
作者：
Barrot, M;Olivier, JDA;Nestler, EJ
通讯作者：
Nestler, EJ
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
2.5
作者：
Hakamata, Y;Iwase, M;Inada, T
通讯作者：
Inada, T
影响因子：
7.4
作者：
Fukuda, Kenichi;Hayashida, Masakazu;Ikeda, Kazutaka
通讯作者：
Ikeda, Kazutaka