Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer
Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer
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DOI：
10.1097/j.pain.0000000000000398
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发表时间：
2016-02-01
期刊：
影响因子：
7.4
通讯作者：
Kalso, Eija
中科院分区：
文献类型：
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作者：
Cajanus, Kristiina;Holmstrom, Emil J.;Kalso, Eija
脂肪酸酰胺水解酶（FAAH）代谢内源性大麻素大麻素，这在伤害感受中具有重要作用。我们研究了常见FAAH单核苷酸多态性（SNPs）在实验性疼痛和术后疼痛中的作用。一千名接受乳腺癌手术的妇女参加了这项研究。测试他们的冷（n = 900）和热疼痛（n = 1000）的敏感性。手术后，他们的疼痛强度和止痛药的消耗被仔细记录。使用MassARRAY平台和全基因组芯片进行FAAH基因分型（n = 926）。使用线性回归模型分析8个FAAH SNPs与9种疼痛表型之间的关联。结果表明，携带2个拷贝的错义变体，将129位的脯氨酸转化为苏氨酸（rs324420），导致冷痛敏感性显著降低，术后镇痛的需要减少。更具体地说，rs324420和另一个高度相关的SNP rs 1571138与冷痛强度显著相关（校正P值，0.0014;隐性模型）。次等位基因纯合子（AA基因型）患者对冷痛的敏感性较低（β = -1.48; 95%CI，-2.14至-0.8）。另外两个SNPs（rs3766246和rs 4660928）与冷痛存在名义关联，而SNPs rs 4141964、rs3766246、rs324420和rs 1571138与羟考酮摄入存在名义关联。总之，FAAH基因变异显示与冷痛敏感性相关，P129 T/rs324420是最可能的致病变异，因为已知其降低FAAH酶活性。相同的变量显示与术后羟考酮消耗量存在名义相关性。然而，我们的结论是有限的，缺乏复制和结果应复制在一个独立的队列。
Fatty acid amide hydrolase (FAAH) metabolizes the endocannabinoid anandamide, which has an important role in nociception. We investigated the role of common FAAH single-nucleotide polymorphisms(SNPs) in experimentally induced and postoperative pain. One thousand women undergoing surgery for breast cancer participated in the study. They were tested for cold (n = 900) and heat pain (n = 1000) sensitivity. After surgery, their pain intensities and analgesic consumption were carefully registered. FAAH genotyping was performed using MassARRAY platform and genome-wide chip (n = 926). Association between 8 FAAH SNPs and 9 pain phenotypes was analyzed using linear regression models. The results showed that carrying 2 copies of a missense variant converting proline at position 129 to threonine (rs324420) resulted in significantly lower cold pain sensitivity and less need for postoperative analgesia. More specifically, rs324420 and another highly correlated SNP, rs1571138, associated significantly with cold pain intensity (corrected P value, 0.0014; recessive model). Patients homozygous for the minor allele (AA genotype) were less sensitive to cold pain (beta = -1.48; 95% CI, -2.14 to -0.8). Two other SNPs (rs3766246 and rs4660928) showed nominal association with cold pain, and SNPs rs4141964, rs3766246, rs324420, and rs1571138 nominal association with oxycodone consumption. In conclusion, FAAH gene variation was shown to associate with cold pain sensitivity with P129T/rs324420 being the most likely causal variant as it is known to reduce the FAAH enzyme activity. The same variant showed nominal association with postoperative oxycodone consumption. Our conclusions are, however, limited by the lack of replication and the results should be replicated in an independent cohort.