靶向基因分型鉴定脑源性神经营养因子基因在慢性术后疼痛中的易感性位点。

Targeted Genotyping Identifies Susceptibility Locus in Brain-derived Neurotrophic Factor Gene for Chronic Postsurgical Pain.

机构信息

From the Department of Anaesthesia and Intensive Care (Y.T., X.L., Z.M., S.K., I.H.T.H., B.J., S.T., T.G., W.K.K.W., M.T.V.C.), Li Ka Shing Institute of Health Sciences (Y.T., X.L., S.K., I.H.T.H., B.J., S.T., S.H.W., J.Y., W.K.K.W., M.T.V.C.), School of Biomedical Sciences (Y.S., C.H.K.C.), and Department of Medicine and Therapeutics (S.H.W., J.Y., W.K.K.W.), Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; the Shandong Provincial Key Laboratory of Mental Disorders, Department of Neurobiology, School of Medicine, Shandong University, Jinan, Shandong, China (M.J., H.Y., Z.C.); the Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (P.L); and the Department of Anaesthesia and Intensive Care, Tuen Mun Hospital, Hong Kong Special Administrative Region, China (B.C.P.C., C.K.M.L.).

出版信息

Anesthesiology. 2018 Mar;128(3):587-597. doi: 10.1097/ALN.0000000000001977.

DOI:10.1097/ALN.0000000000001977

PMID:29120944

Abstract

BACKGROUND

The purpose of this study was to evaluate the association between single-nucleotide polymorphisms and chronic postsurgical pain.

METHODS

Using GoldenGate genotyping assays, we genotyped 638 polymorphisms within 54 pain-related genes in 1,152 surgical patients who were enrolled in our Persistent Pain after Surgery Study. Patients were contacted by phone to determine whether they had chronic postsurgical pain at 12 months. Polymorphisms identified were validated in a matched cohort of 103 patients with chronic postsurgical pain and 103 patients who were pain free. The functions of targeted polymorphisms were tested in an experimental plantar incisional nociception model using knock-in mice.

RESULTS

At 12 months after surgery, 246 (21.4%) patients reported chronic postsurgical pain. Forty-two polymorphisms were found to be associated with chronic postsurgical pain, 19 decreased the risk of pain, and 23 increased the risk of pain. Patients carrying allele A of rs6265 polymorphism in brain-derived neurotrophic factor (BDNF) had a lower risk of chronic postsurgical pain in the discovery and validation cohorts, with an adjusted odds ratio (95% CI) of 0.62 (0.43 to 0.90) and 0.57 (0.39 to 0.85), respectively. Age less than 65 yr, male sex, and prior history of pain syndrome were associated with an increased risk of pain. Genetic polymorphisms had higher population attributable risk (7.36 to 11.7%) compared with clinical risk factors (2.90 to 5.93%). Importantly, rs6265 is a substitution of valine by methionine at amino acid residue 66 (Val66Met) and was associated with less mechanical allodynia in BDNF mice compared with BDNF group after plantar incision.

CONCLUSIONS

This study demonstrated that genetic variant of BDNF rs6265G>A is associated with decreased risk of chronic postsurgical pain.

摘要

背景

本研究旨在评估单核苷酸多态性与慢性术后疼痛之间的关联。

方法

使用 GoldenGate 基因分型检测，我们对纳入我们的术后持续性疼痛研究中的 1152 名手术患者的 54 个与疼痛相关的基因中的 638 个多态性进行基因分型。通过电话联系患者，以确定他们在 12 个月后是否患有慢性术后疼痛。在慢性术后疼痛的 103 名患者和无痛的 103 名患者的匹配队列中验证了鉴定的多态性。使用 knock-in 小鼠在实验性足底切口伤害感受模型中测试靶向多态性的功能。

结果

手术后 12 个月，246（21.4%）名患者报告有慢性术后疼痛。发现 42 个多态性与慢性术后疼痛相关，其中 19 个降低疼痛风险，23 个增加疼痛风险。在发现和验证队列中，脑源性神经营养因子（BDNF）rs6265 多态性的等位基因 A 携带者患慢性术后疼痛的风险较低，调整后的优势比（95%置信区间）分别为 0.62（0.43 至 0.90）和 0.57（0.39 至 0.85）。年龄小于 65 岁、男性和既往疼痛综合征史与疼痛风险增加相关。遗传多态性的人群归因风险（7.36%至 11.7%）高于临床危险因素（2.90%至 5.93%）。重要的是，rs6265 是氨基酸残基 66 处缬氨酸被蛋氨酸取代（Val66Met），与 BDNF 小鼠相比，足底切口后 BDNF 组的机械性痛觉过敏程度较低。