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

Yuanyuan Tian, B.Med., M.Med., Ph.D.; Xiaodong Liu, B.Sc., M.Eng., Ph.D.; Mingzhong Jia, B.Sc., M.Phil.; Hui Yu, Ph.D.; Peter Lichtner, Ph.D.; Yujian Shi, Ph.D.; Zhaoyu Meng, B.Sc., M.Phil., Ph.D.; Shanglong Kou, B.Sc., M.Sc., Ph.D.; Idy H. T. Ho, B.Sc., Ph.D.; Bo Jia, B.Med., M.Sc.; Benny C. P. Cheng, B.Sc., M.B., B.S., F.H.K.C.A., F.H.K.A.M.; Carmen K. M. Lam, M.B., B.S., F.A.N.Z.C.A., F.H.K.C.A., F.H.K.A.M.; Sharon Tsang, M.B., Ch.B., Ph.D.; Sunny H. Wong, M.B., Ch.B., D.Phil., M.R.C.P.; Jun Yu, M.D., Ph.D.; Christopher H. K. Cheng, B.Sc., Ph.D.; Tony Gin, M.D., F.R.C.A., F.A.N.Z.C.A., F.H.K.C.A., F.H.K.A.M.; William K. K. Wu, M.Phil., Ph.D., F.R.C.Path.; Zheyu Chen, Ph.D.; Matthew T. V. Chan, M.B., B.S., Ph.D., F.A.N.Z.C.A., F.H.K.C.A., F.H.K.A.M.

Disclosures

Anesthesiology. 2018;128(3):587-597. 

In This Article

Abstract and Introduction

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 Met/Met mice compared with BDNF Val/Val group after plantar incision.

Conclusions: This study demonstrated that genetic variation of BDNF is associated with an increased risk of chronic postsurgical pain.

Introduction

POSTOPERATIVE pain is an inevitable consequence of surgery. As wound healing is completed with time, it is anticipated that pain will be reduced accompanied by a return of function. However, some patients continue to suffer persistent pain over the surgical wound, which could not be explained by disease recurrence.[1,2] This disease entity, currently known as chronic postsurgical pain, has been estimated to affect 9.2 to 80.0% of patients having a variety of surgery.[3–8] Considering that more than 230 million surgeries are performed each year worldwide,[9] the data would imply that millions of patients will continue to suffer wound pain, months to years after their surgery.

Although peripheral nerve injury, severe acute postoperative pain, and psychosocial factors are thought to increase the risk for chronic postsurgical pain,[5,10] considerable efforts have been made to identify the genetic determinants of pain.[11] For instance, single-nucleotide polymorphisms (SNPs) of catecholamine-O-methyltransferase (COMT) altered pain sensitivity in experimental settings.[12] Similarly, using quantitative trait locus mapping, two variant alleles of the melanocortin-1 receptor gene (MC1R) were associated with greater analgesia from κ-opioid in women.[13] Other investigators have found that genetic polymorphism of interleukin-1β is involved in allodynia and possibly postsurgical neuropathic and inflammatory pain.[14] Multiple polymorphisms within GTP cyclohydrolase (GCH1) have also been found to predict chronic back pain syndrome.[15] In addition, our recent study found that patients with AA genotypes at polymorphisms, rs2070697 and rs2236742, in cathepsin G (CTSG) gene significantly reduced the risk for chronic postsurgical pain.[16] We therefore hypothesized that genetic variations are associated with the development of chronic postsurgical pain. In the current study, we analyzed the association of 638 SNPs located in 54 pain-related genes and explored the risk factors associated with chronic postsurgical pain in the first 1,873 patients enrolled in our Persistent Pain after Surgery Study. We also investigated the functional role of an identified SNP (brain-derived neurotrophic factor, BDNF) in an experimental nociception model using knock-in mice.

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