DataSheet1_Short Tandem Repeat Variation in the CNR1 Gene Associated With Analgesic Requirements of Opioids in Postoperative Pain Management.xlsx

Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) that have been identified at approximately 0.7 and 0.5 million loci in the human genome, respectively, are highly multi-allelic variations rather than single-nucleotide polymorphisms. The number of repeats of more than a few thousand STRs was associated with the expression of nearby genes, indicating that STRs are influential genetic variations in human traits. Analgesics act on the central nervous system via their intrinsic receptors to produce analgesic effects. In the present study, we focused on STRs and VNTRs in the CNR1, GRIN2A, PENK, and PDYN genes and analyzed two peripheral pain sensation-related traits and seven analgesia-related traits in postoperative pain management. A total of 192 volunteers who underwent the peripheral pain sensation tests and 139 and 252 patients who underwent open abdominal and orthognathic cosmetic surgeries, respectively, were included in the study. None of the four STRs or VNTRs were associated with peripheral pain sensation. Short tandem repeats in the CNR1, GRIN2A, and PENK genes were associated with the frequency of fentanyl use, fentanyl dose, and visual analog scale pain scores 3 h after orthognathic cosmetic surgery (Spearman’s rank correlation coefficient ρ = 0.199, p = 0.002, ρ = 0.174, p = 0.006, and ρ = 0.135, p = 0.033, respectively), analgesic dose, including epidural analgesics after open abdominal surgery (ρ = −0.200, p = 0.018), and visual analog scale pain scores 24 h after orthognathic cosmetic surgery (ρ = 0.143, p = 0.023), respectively. The associations between STRs in the CNR1 gene and the frequency of fentanyl use and fentanyl dose after orthognathic cosmetic surgery were confirmed by Holm’s multiple-testing correction. These findings indicate that STRs in the CNR1 gene influence analgesia in the orofacial region.

分别在人类基因组约70万个和50万个基因座中被鉴定得到的短串联重复序列（short tandem repeats, STRs）与可变数目串联重复序列（variable number of tandem repeats, VNTRs），均属于高度多等位基因变异，而非单核苷酸多态性。逾千个STRs的重复单元数目与邻近基因的表达水平相关，这表明STRs是影响人类性状的重要遗传变异。

镇痛药通过其内在受体作用于中枢神经系统以发挥镇痛功效。本研究聚焦于CNR1、GRIN2A、PENK及PDYN基因中的STRs与VNTRs，分析了术后疼痛管理场景下的2种外周疼痛感知相关表型与7种镇痛相关表型。本研究共纳入192名完成外周疼痛感知测试的志愿者，以及分别接受开放性腹部手术与正颌美容手术的139名和252名患者。

上述4种STRs与VNTRs均未与外周疼痛感知存在关联。CNR1、GRIN2A与PENK基因中的短串联重复序列分别与正颌美容术后3小时的芬太尼使用频率、芬太尼剂量及视觉模拟评分（visual analog scale, VAS）疼痛评分（斯皮尔曼等级相关系数ρ分别为0.199、p=0.002；0.174、p=0.006；0.135、p=0.033）、开放性腹部手术后含硬膜外镇痛药在内的镇痛药物剂量（ρ=-0.200，p=0.018），以及正颌美容术后24小时的视觉模拟评分疼痛评分（ρ=0.143，p=0.023）存在关联。经霍姆（Holm）多重检验校正后，CNR1基因中的短串联重复序列与正颌美容手术后芬太尼使用频率及芬太尼剂量的关联得到验证。上述研究结果表明，CNR1基因中的短串联重复序列可影响口面部区域的镇痛反应。