Association Between Polymorphisms in the Purinergic P2Y12 Receptor Gene and Severity of Both Cancer Pain and Postoperative Pain
Association Between Polymorphisms in the Purinergic P2Y12 Receptor Gene and Severity of Both Cancer Pain and Postoperative Pain
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DOI：
10.1093/pm/pnx102
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发表时间：
2018-02
期刊：
影响因子：
3.1
通讯作者：
M. Sumitani;D. Nishizawa;M. Nagashima;K. Ikeda;H. Abe;Ryoji Kato;H. Ueda;Yoshitsugu Yamada
中科院分区：
文献类型：
--
作者：
M. Sumitani;D. Nishizawa;M. Nagashima;K. Ikeda;H. Abe;Ryoji Kato;H. Ueda;Yoshitsugu Yamada
背景尽管阿片类药物广泛用于治疗癌症疼痛，但多项调查的结果一致表明，疼痛在一些恶性疾病患者中仍然普遍存在。嘌呤能 P2Y12 受体是导致小胶质细胞激活和痛觉过敏行为的主要位点，被认为是预防临床疼痛状况恶化的关键调节因子。 P2RY12 基因的遗传变异可能导致疼痛和阿片类药物敏感性的个体差异。方法 我们对整个 P2RY12 基因的 31 个单核苷酸多态性 (SNP) 进行了基因分型，并将基因型与日本癌痛患者 (N = 90) 的疼痛测量和阿片类药物需求进行了比较。最有希望的 SNP 与疼痛严重程度的关联通过对额外的术后疼痛患者队列 (N = 355) 进行基因分型来验证。结果 P2RY12 基因的 5 个 SNP（rs3732765、rs9859538、rs17283010、rs11713504 和 rs10935840）与癌痛严重程度显着相关，尽管这 5 个 SNP 的每种基因型的阿片类药物需求量相当。这些 SNP 的等位基因代表 P2RY12 基因的一个绝对连锁不平衡区块。在第二项术后疼痛关联研究中，携带 rs3732765 SNP 次要 T 等位基因的受试者与不携带该等位基因的受试者相比，表现出更强烈的术后 24 小时疼痛，尽管基于体重的术后 24 小时阿片类药物总消耗量相当。结论 P2RY12 基因的多态性可以预测癌症和术后疼痛严重程度的个体差异；这可能是由于神经元-神经胶质细胞相互作用导致伤害性神经元功能改变所致。
Background Despite the widespread use of opioids for the treatment of cancer pain, results from several surveys consistently show that pain is still prevalent in some patients with malignant diseases. The purinergic P2Y12 receptor is a primary site leading to microglial activation and hyperalgesic pain behaviors and is considered a key regulator in the prevention of the aggravation of clinical pain conditions. Genetic variability in the P2RY12 gene may contribute to individual differences in pain and opioid sensitivity. Methods We genotyped 31 single nucleotide polymorphisms (SNPs) throughout the P2RY12 gene and compared genotypes against pain measurements and opioid requirements in Japanese cancer pain patients (N = 90). The most promising SNP association with pain severity was validated by genotyping an additional postoperative pain patient cohort (N = 355). Results Five SNPs (rs3732765, rs9859538, rs17283010, rs11713504, and rs10935840) of the P2RY12 gene were significantly associated with cancer pain severity, although opioid requirements were comparable in each genotype of the five SNPs. The alleles of these SNPs represented one absolute linkage disequilibrium block of the P2RY12 gene. In the second association study of postoperative pain, subjects carrying the minor T allele of the rs3732765 SNP demonstrated more intense 24-hour postoperative pain compared with subjects not carrying this allele although total 24-hour postoperative opioid consumptions based on weight were comparable. Conclusions Polymorphisms of the P2RY12 gene may predict individual differences in both cancer and postoperative pain severity; this might be caused by functional alteration of nociceptive neurons through neuron-glia interaction.