TY  - JOUR
AB  - 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 variation of BDNF is associated with an increased risk of chronic postsurgical pain.
AU  - Tian, Y.*
AU  - Liu, X.*
AU  - Jia, M.*
AU  - Yu, H.*
AU  - Lichtner, P.
AU  - Shi, Y.*
AU  - Meng, Z.*
AU  - Kou, S.*
AU  - Ho, I.H.T.*
AU  - Jia, B.*
AU  - Cheng, B.C.P.*
AU  - Lam, C.K.M.*
AU  - Tsang, S.H.*
AU  - Wong, S.H.*
AU  - Yu, J.*
AU  - Cheng, C.H.K.*
AU  - Gin, T.*
AU  - Wu, W.K.K.*
AU  - Chen, Z.*
AU  - Chan, M.T.V.*
AU  - Mou, A.*
AU  - Tsang, M.W.*
AU  - Tsang, M.W.M.*
AU  - Kwan, R.*
AU  - Wong, E.*
AU  - Yau, K.*
AU  - Lok, A.*
AU  - Lee, E.*
AU  - Fung, B.*
AU  - Lam, L.*
AU  - Chan, C.S.*
C1  - 52309
C2  - 43892
SP  - 587-597
TI  - Targeted genotyping identifies susceptibility locus in brain-derived neurotrophic factor gene for chronic postsurgical pain.
JO  - Anesthesiology
VL  - 128
PY  - 2018
SN  - 0003-3022
ER  - 

TY  - JOUR
AB  - BACKGROUND: Proteases have been shown to modulate pain signaling in the spinal cord and may contribute to the development of chronic postsurgical pain. By using peripheral inflammation in rats as a chronic pain model, the authors identified the deregulation of proteases and their inhibitors as a hallmark of chronic pain development using a genome-wide screening approach. METHODS: A microarray analysis was performed and identified spinal cathepsin G (CTSG) as the most up-regulated gene in rats with persistent hyperalgesia after intraplantar injection of complete Freund's adjuvant (n = 4). Further experiments were performed to elucidate the mechanisms of CTSG-induced hyperalgesia by intrathecally applying specific CTSG inhibitor (n = 10). The authors also evaluated the association between CTSG gene polymorphisms and the risk of chronic postsurgical pain in 1,152 surgical patients. RESULTS: CTSG blockade reduced heat hyperalgesia, accompanied by a reduction in neutrophil infiltration and interleukin 1β levels in the dorsal horns. In the gene association study, 246 patients (21.4%) reported chronic postsurgical pain at 12-month follow-up. Patients with AA genotypes at polymorphisms rs2070697 (AA-15.3%, GA-24.1%, and GG-22.3%) or rs2236742 (AA-6.4%, GA-20.4%, and GG-22.6%) in the CTSG gene had lower risk for chronic postsurgical pain compared with wild-types. The adjusted odds ratios were 0.67 (95% CI, 0.26 to 0.99) and 0.34 (95% CI, 0.21 to 0.98), respectively. CONCLUSIONS: This study demonstrated that CTSG is a pronociceptive mediator in both animal model and human study. CTSG represents a new target for pain control and a potential marker to predict patients who are prone to develop chronic pain after surgery.
AU  - Liu, X.*
AU  - Tian, Y.*
AU  - Meng, Z.*
AU  - Chen, Y.*
AU  - Ho, I.H.*
AU  - Choy, K.W.*
AU  - Lichtner, P.
AU  - Wong, S.H.*
AU  - Yu, J.*
AU  - Gin, T.*
AU  - Wu, W.K.*
AU  - Cheng, C.H.*
AU  - Chan, M.T.*
C1  - 46574
C2  - 37704
CY  - Philadelphia
SP  - 838-850
TI  - Up-regulation of cathepsin G in the development of chronic postsurgical pain: An experimental and clinical genetic study.
JO  - Anesthesiology
VL  - 123
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2015
SN  - 0003-3022
ER  - 

TY  - JOUR
AB  - BACKGROUND: Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gαs enhances inotropic responses to adrenergic stimulation and improves survival in mice under βAR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding Gαs, with the greatest Gαs protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants result in altered mortality in patients after coronary artery bypass graft surgery, particularly in those receiving βAR blockade. METHODS: This prospective analysis included 1,627 European ancestry patients undergoing primary coronary artery bypass graft surgery. Patients were genotyped for two GNAS haplotype tagging single-nucleotide polymorphisms defining three major haplotypes. Up to 5-yr all-cause mortality was estimated using a Cox proportional hazard model; hazard ratios and 95% CIs were calculated while adjusting for demographics, clinical covariates, and the new EuroSCORE II. RESULTS: Univariate analysis revealed haplotype-dependent 5-yr mortality rates (*1/*1: 18.9%, *2/*1: 13.7%, *2/*2: 9.3%, *3/*1: 10.6%, *3/*2: 9.1%, and *3/*3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype *1 carriers showed a doubled risk for death (hazard ratio, 2.2; 95% CI, 1.2 to 3.8; P = 0.006). Considering only patients receiving βAR blockers (n = 1,267), the adjusted risk of death even tripled (hazard ratio, 3.0; 95% CI, 1.5 to 6.1; P = 0.002). CONCLUSIONS: GNAS haplotypes independently associate with an increased risk of death after primary coronary artery bypass graft surgery. These results are most pronounced in patients receiving βAR blockers, strengthening the rationale for personalized treatment, to decrease medication side effects and improve outcomes.
AU  - Frey, U.H.*
AU  - Muehlschlegel, J.D.*
AU  - Ochterbeck, C.*
AU  - Fox, A.A.*
AU  - Shernan, S.K.*
AU  - Collard, C.D.*
AU  - Lichtner, P.
AU  - Peters, J.*
AU  - Body, S.*
C1  - 31110
C2  - 34127
CY  - Philadelphia
SP  - 1109-1117
TI  - GNAS gene variants affect β-blocker-related survival after coronary artery bypass grafting.
JO  - Anesthesiology
VL  - 120
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0003-3022
ER  - 

TY  - JOUR
AB  - BACKGROUND: Ventricular dysfunction (VnD) after primary coronary artery bypass grafting is associated with increased hospital stay and mortality. Natriuretic peptides have compensatory vasodilatory, natriuretic, and paracrine influences on myocardial failure and ischemia. The authors hypothesized that natriuretic peptide system gene variants independently predict risk of VnD after primary coronary artery bypass grafting. METHODS: A total of 1,164 patients undergoing primary coronary artery bypass grafting with cardiopulmonary bypass at two institutions were prospectively enrolled. After prospectively defined exclusions, 697 patients of European descent (76 with VnD) were analyzed. VnD was defined as need for at least 2 new inotropes and/or new mechanical ventricular support after coronary artery bypass grafting. A total of 139 haplotype-tagging single nucleotide polymorphisms (SNPs) within 7 genes (NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, CORIN) were genotyped. SNPs univariately associated with VnD were entered into logistic regression models adjusting for clinical covariates predictive of VnD. To control for multiple comparisons, permutation analyses were conducted for all SNP associations. RESULTS: After adjusting for clinical covariates and multiple comparisons within each gene, seven NPPA/NPPB SNPs (rs632793, rs6668352, rs549596, rs198388, rs198389, rs6676300, rs1009592) were associated with decreased risk of postoperative VnD (additive model; odds ratios 0.44-0.55; P = 0.010- 0.036) and four NPR3 SNPs (rs700923, rs16890196, rs765199, rs700926) were associated with increased risk of postoperative VnD (recessive model; odds ratios 3.89-4.28; P = 0.007-0.034). CONCLUSIONS: Genetic variation within the NPPA/NPPB and NPR3 genes is associated with risk of VnD after primary coronary artery bypass grafting. Knowledge of such genotypic predictors may result in better understanding of the molecular mechanisms underlying postoperative VnD.
AU  - Fox, A.A.*
AU  - Collard, C.D.*
AU  - Shernan, S.K.*
AU  - Seidman, C.E.*
AU  - Seidman, J.G.*
AU  - Liu, K.Y.*
AU  - Muehlschlegel, J.D.*
AU  - Perry, T.E.*
AU  - Aranki, S.F.*
AU  - Lange, C.*
AU  - Herman, D.S.*
AU  - Meitinger, T.
AU  - Lichtner, P.
AU  - Body, S.C.*
C1  - 1334
C2  - 26625
CY  - United States
SP  - 738-747
TI  - Natriuretic peptide system gene variants are associated with ventricular dysfunction after coronary artery bypass grafting.
JO  - Anesthesiology
VL  - 110
IS  - 4
PB  - American Society of Anesthesiologists
PY  - 2009
SN  - 0003-3022
ER  -