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. Author manuscript; available in PMC: 2021 Jan 1.
Published in final edited form as: J Pain. 2019 May 23;21(1-2):2–24. doi: 10.1016/j.jpain.2019.05.008

Table 2:

Description of genes, variants, genetic association and covariates in the studies evaluated for the systematic review

Author/Year Gene SNP Haplotype SNPs Reference Allele/genotype Frequency (Cases versus (vs) controls) when reported OR 95% CI p-value Genetic model Covariates and ancestry
LL UL
Sia 2010 ABCB1 C3435T T 1.66 1.03 2.67 0.03 A No covariates described, no ancestry
C1236T NS
G2677T/A NS
Costigan 2010 KCNS1 (different cohorts) rs734784 (LD) G (Val). 45% vs: 22% 2.4 (RR) 1.2 4.5 0.003 R Age, gender, population stratification;
LD: Lumbar discectomy cohort
ILAP: Israel limb amputation pain
DLA: Denmark limb amputation
PMP: Israel post-mastectomy pain
rs13043825 (LD) 0.03
rs734784 (ILAP) G 0.0033
rs13043825 (ILAP) 0.056
rs734784 (DLA) G 0.01
rs734784 (PMP) G 0.74
rs734784 (entire cohort) G (Val) 1.14 e−08
Nissenbaum 2010 CACNG2 rs4820242 0.02 Multiplicative ethnicity, number of years since operation, chemotherapeutic treatment, and surgery type (mastectomy or lumpectomy
rs2284015 0.02
rs2284017 0.04
rs2284018 0.05
rs1883988 0.03
rs4820242, rs2284015, rs2284017 A-C-C 1.65 0.01
Hickey 2011 COMT rs4680 A: 11% vs. 39% AA; 37.5% vs 37.5% AG NR - - 0.06 NR Covariates not reported. No ancestry
GCH1 rs8007267, rs10483639, rs3783641 ATG NR - - 1
Lee 2011 COMT
GCH1		 rs4680, rs4818, rs6269 A, G, G
T		 - - - NS NR Psychological and clinical covariates; no ancestry*Relative risk
OPRM1 rs8007267
rs1799971		 G
CACNA2D2 rs5030977 GG (72.3% vs 70.2%) 1.14* 0.66 2 0.603 R
GRIK rs6691840 TT (59.6% vs 51.8%) 1.16* 0.7 1.92 0.247 R
BDNF rs6265 GG (63.8% vs 62.3%) 0.96* 0.58 1.61 0.34 R
OPRM1 rs1799971 AA (70.2% vs 70.2%) 0.98* 0.57 1.68 0.935 R
Sorge 2012 P2X7R rs208294 A 1.17 Beta values of regression with pain intensity reported 0.003 NR age at surgery, and time since the operation, which robustly affected pain traits in this cohort); no ancestry
rs208296 T −1.21 0.003
rs7958311 A −1.19 0.006
rs208294
rs208296
rs7958311		 p.H155Y, c.533+630C>T, p.R270H
ATA 1.58 0.186
GTA −0.71 0.003
ACA −0.48 0.354
GCA 0.08 0.922
GTG −0.41 0.211
ACG 0.7 0.001
GCG 0.06 0.803
Hegarty 2012 GCH1 rs3783641 T (72% vs 75%) 0.07 Pearson’s chi square values reported 0.77 Allelic or genotype model Unadjusted. No ancestry
TT/AA/AA 0.14 0.93
rs8007627 T (22% vs 44%) 4.86 0.02
CC/CT/TT 4.23 0.12
rs10483639 C (77% vs 36%) 0.8 0.37
GG/CG/CC 0.92 0.63
OPRM1 rs1799971 A (72% vs 57%) 0.29 0.58
AA/AG/GG 0.23 0.88
COMT rs4680 G (28% vs. 43%) 1.85 0.17
AA/AG/GG 3.7 0.15
CYP2D6 rs3892097 T (13% vs. 23%) 1.63 0.2
CC/CT/TT 2.13 0.34
Lebe 2013 5HTR1A rs6295 G 3.909# # main genetic effect in interaction model <0.05 age, pain intensity, and depression; no ancestry
5HTR2A rs6311 G 0.047# NS
Kolesnikov 2013 COMT rs4680 A: 10/35 AA, 16/35 AG vs 12/67 AA, 39/67 AG - - - 0.74, 0.44, 0.79 A, D, R age, sex, and baseline pain score; no ancestry
OPRM1 rs1799971 G: 4/35 (AG+GG) vs 14/67 - - - 0.31, 0.22, 0.95
Dominguez 2013 HLA-DRB1 1 14% vs 13% 1.11 0.62 1.99 NS Age, smoking, treatment status; No ancestry
3 10% vs 17% 0.53 0.29 0.98 NS
4 24% vs 12% 2.28 1.32 3.96 0.004 D
7 8% vs 8% 0.94 0.45 1.97 NS
8 6% vs 2% 2.89 0.9 9.24 NS
9 1% vs 2% 0.5 0.09 2.76 NS
11 2% vs 4% 0.42 0.11 1.66 NS
12 2% vs 3% 0.67 0.19 2.4 NS
13 15% vs 14% 1.06 0.6 1.87 NS
14 4% vs 3% 1.19 0.39 3.6 NS
15 14% vs 19% 0.72 0.42 1.24 NS
16 0% vs 2% 0.25 0.03 2.25 NS
DQB1*03:02 20% vs 7% 3.24 <0.003 D
DQB1⁄03:02 – DRB1⁄04 3.16 1.61 6.22 <0.001
Stephens 2014 IFNG1 rs2069727 G FE 0.025 R ^Chi-square genomic estimates of and self-reported race/ethnicity (ie, white, black, Asian, Hispanic/mixed ethnic background/other), occurrence of pain in the affected breast prior to surgery, and severity of average postoperative pain
rs2069718 T 10.09^ 0.006 A
HapA5 6.58^ 0.037
IL1R1 rs3917332 T FE 0.037 D
IL1R2 rs11674595 C FE 0.041 R
IL4 rs2243248 G FE 0.033 D
IL10 rs3024498 G FE 0.015 D
rs1878672 C FE 0.029 D
rs3024491 T FE 0.035 D
HapA8 6.39^ 0.041
IL13 rs1881457 C FE 0.043 D
rs1800925 T FE 0.007 D
rs1295686 A FE 0.014 D
rs20541 T 7.81^ 0.017 A
HapA1 8.7^ 0.013
NFKB1 rs4648141 A FE 0.041 R
IL1R2 rs11674595 C: TT+TC>CC 36.07 2.02 643.37 0.015 D
HapA8: rs3024505-rs3024498-rs3024496-rs1878672-rs1518111-rs1518110-rs3024491 0, 1, or 2 doses of the C-G-C-G-A-T-T haplotype 0.21 0.05 0.91 0.037
Rut 2014 COMT rs4680 A: GG vs GA+AA (MAF NR) 0.053 R Age, sex, change in pain score; no ancestry; p-value for pain score change for back pain from preoperative to postoperative is reported.
rs4680 A: AA vs GG+GA 0.87 D
rs4818 T: TT vs AT+AA 0.27 R
rs4818 T: AA vs AT+TT 0.08042 D
rs4633 T: GG vs GC+CC 0.91 R
rs4633 T: CC vs GC+GG 0.053 D
rs6269 G: AA vs AG+GG 0.16 D
rs6269 G: GG vs AG+AA 0.0042 R
Multiple regression model
rs4680 A −1.2 0.046 D
Haplotype L (rs6269, rs4633, rs4818, rs4680) A_C_C_G −1.3 0.014
rs4633 T −1.45 0.0032 R
Liu 2015 Cathepsin (CTSG) rs2236742 A: (GG 22.6%, GA 20.4%, AA 6.4% in cases; controls NR) 0.34 0.21 0.98 0.043 Genotype model age, sex, smoking habit, employment history, education level, prior pain syndrome, and severity of acute pain after index surgery; no ancestry
rs2070697 AA (GG 22.3%, GA 24.1%, AA 15.3% cases) 0.67 0.26 0.99 0.044
Belfer 2015 COMT rs6269, rs4633, rs4818 GCG 0.57 0.35 0.95 0.031 surgical treatment (open vs laparoscopic), preoperative AAS score, preoperative pain response to the 47°C heat stimuli, difference (postoperative 2 preoperative) of warmth detection in groin, preoperative HADS anxiety score, preoperative HADS depression score, and Pain Catastrophizing Scale score; No ancestry.
ATC 1.66 0.041
ACC 0.67 0.25 1.82 0.431
GCH1 rs3783641, rs8007267 AT 0.53 0.27 1.07 0.076
AC 0.46 0.1 2.11 0.321
TC 1.94 0.043
COMT rs6269 G (30% vs 40.3%) 0.59 0.37 0.96 0.034 A
rs4633 C (35.5% vs 47.3%) 0.53 0.32 0.88 0.014 A
rs4818 G (30.9% vs 39.8%) 0.63 0.39 1.03 0.063 A
GCH1 rs3783641 A (14.5% vs 22.1%) 0.57 0.31 1.07 0.079 A
GCH1 rs8007267 T (13% vs 23.2%) 0.51 0.26 1.02 0.057 A
Montes 2015 OPRD1 rs1042114 G 1.2 0.93 1.55 0.1636 different inheritance models were tested in autosomic SNPs by comparing each genotype against the combination of the remaining two Age, SF-12 = Short Form Health Survey-12 physical and mental summary scores, preoperative pain score; No ancestry
rs533123 C 1 0.8 1.25 0.9907
GRIK3 rs6691840 A 1.04 0.85 1.27 0.7091
FAAH/NSUN4 rs932816 A 1.16 0.96 1.41 0.1251
FAAH rs4141964 G 1.02 0.85 1.22 0.8462
rs2295633 C 1 0.83 1.21 0.9675
Unknown gene A 1.11 0.92 1.33 0.2757
PTGS2 rs5275 C 1.03 0.85 1.24 0.8001
IL19/IL10 rs1800896 A 1.04 0.87 1.24 0.675
POMC rs934778 T 1.03 0.86 1.24 0.7558
SCN9A rs6746030 A 1.01 0.78 1.32 0.9196
rs6747673 A 1.08 0.9 1.28 0.4144
rs9646771 C 1.04 0.86 1.25 0.6842
GABRA4 rs7678338 T 1.05 0.86 1.27 0.6507
rs7689605 A 1.08 0.78 1.49 0.6494
GABRB1 rs10028945 A 1.01 0.84 1.23 0.8924
SLC6A3/CLPTM1L rs12516948 G 1.04 0.87 1.24 0.6565
SLC6A3 rs40184 A 1.01 0.85 1.2 0.9359
rs403636 G 1.17 0.92 1.47 0.1926
rs6350 C 1.13 0.81 1.57 0.4853
GABRB2/GABRA6 rs3816596 T 1.05 0.87 1.26 0.6129
GABRA1/LOC100287123 rs12658835 G 1.05 0.86 1.28 0.6454
ATXN1 rs179997 A 1.2 1 1.44 0.0473
TNF/LTA rs1800629 G 1.14 0.87 1.5 0.3355
OPRM1 rs1799971 A 1.12 0.89 1.41 0.337
rs563649 A 1.04 0.72 1.5 0.8261
OPRK1 rs702764 T 1.04 0.81 1.33 0.7637
rs997917 C 1.09 0.9 1.33 0.3819
PENK rs3839874 T 1.11 0.93 1.32 0.2525
rs1975285 C 1.19 0.96 1.47 0.1082
TRPA1 rs11988795 C 1.01 0.84 1.22 0.8807
BDNFOS rs6265 G 1.12 0.91 1.37 0.295
BDNF rs2049046 T 1.14 0.96 1.36 0.1426
KIF18A/BDNF rs908867 G 1.28 0.93 1.77 0.127
DRD2 rs6277 T 1.04 0.87 1.24 0.6926
rs1076560 C 1.08 0.83 1.41 0.5758
rs2734837 G 1.03 0.85 1.24 0.7506
rs11608185 T 1.03 0.85 1.24 0.7529
rs4936272 C 1.02 0.85 1.21 0.864
rs4648317 T 1.35 1.05 1.74 0.0186
rs4322431 T 1.09 0.9 1.33 0.3671
TMPRSS5/DRD2 rs1799978 A 1.03 0.69 1.53 0.8962
TMPRSS5/DRD2 rs12364283 G 1.58 1.11 2.23 0.0102
Unknown gene* rs6693882 T 1.17 0.97 1.4 0.1005
SLCO1B3 rs4149117 G 1.09 0.84 1.41 0.5382
SLCO1A2 rs11568563 A 1.23 0.87 1.74 0.2388
NFKBIA rs8904 T 1.21 1.01 1.44 0.0394
SAMD4A/GCH1 rs10483639 C 1.24 0.98 1.57 0.0713
SAMD4A/GCH1 rs7142517 C 1.09 0.9 1.31 0.3649
GCH1 rs752688 T 1.27 1 1.6 0.0514
rs4411417 C 1.27 1 1.62 0.0458
rs9671371 T 1.18 0.97 1.44 0.1016
rs12147422 T 1.17 0.87 1.57 0.3107
rs8004445 G 1.19 0.88 1.6 0.2536
rs998259 C 1 0.82 1.22 0.9864
rs3783641 A 1.23 0.97 1.56 0.0807
WDHD1 rs8007267 T 1.15 0.9 1.47 0.2502
SLC6A2 rs40434 C 1.15 0.96 1.38 0.139
SLC6A2 rs36024 C 1.12 0.94 1.34 0.2056
SLC6A2 rs36017 G 1.14 0.96 1.36 0.141
TRPV1 rs8065080 C 1 0.84 1.2 0.9945
CCDC55 rs1979572 C 1.02 0.86 1.22 0.7896
SLC6A4 rs4325622 T 1 0.84 1.2 0.9607
SLC6A4 rs140701 G 1.05 0.88 1.26 0.557
SLC6A4 rs2066713 C 1.07 0.89 1.29 0.4839
MC4R/LOC728115 rs9966412 C 1.11 0.86 1.44 0.4191
Unknown rs2562456 C 1.1 0.9 1.35 0.3402
B9D2/TGFB1 rs1800469 C 1.05 0.88 1.27 0.5785
COMT rs4646312 C 1.09 0.91 1.3 0.3568
rs6269 G 1.06 0.89 1.27 0.5077
rs4680 G 1.05 0.88 1.25 0.6067
MAOA rs3788862 A 1.1 0.85 1.42 0.4551
rs2283724 G 1.08 0.85 1.37 0.5271
rs1800659 C 1.03 0.8 1.31 0.8307
rs979606 G 1.03 0.8 1.33 0.8108
rs979605 T 1.03 0.8 1.33 0.7978
Wieskopf JS CHRNA6 rs7828365 TT (8/325 vs 0.12% in general population) 12 SEM 1.1 0.03 D patients’ age, surgery type, and activity assessment scale (AAS) score (0% if no pain-related activity impairment was reported, and 100% for maximum impairment) at baseline; no ancestry
Langford 2015 Multiple regression model
KCND2 rs17376373 0.12 0.017 0.814 0.030 D population substructure (ie, race/ethnicity), occurrence of pain in the affected breast before surgery, hardness in affected breast before surgery, and reexcision or mastectomy performed within 6 mo after the initial surgery for breast cancer
KCNJ3 HapA2 rs3111020 - rs11895478 G-A 0.11 0.027 0.438 0.002
KCNJ6 rs2835925 C 19.28 3.299 112.713 0.001 G
KCNK9 rs2014712 T 9.85 1.099 88.268 0.041 R
Univariate regression X2 p-value
KCNA1 rs4766311 T 1.02 0.601 A
KCND2 rs17376373 G FE 0.009 D
rs702414 C FE 0.023 R
rs802340 T 8.74 0.013 A
rs12706292 G FE 0.03 D
rs1072198 G 1.09 0.58 A
KCNS1 rs734784 G 0.73 0.693 A
HapB1 0.73 0.693
KCNJ3 rs6435329 T FE 0.005 D
rs11895478 T FE 0.001 D
rs3106653 C FE 0.004 D
rs3111006 T FE 0.012 R
rs12471193 G 6.11 0.047 A
rs7574878 G FE 0.01 D
rs12995382 C FE 0.031 D
rs13398937 G 1.63 0.444 A
rs2591157 G 0.02 0.992 A
rs17641121 C 1.99 0.37 A
rs4467223 A 1.26 0.533 A
HapA2 11.69 0.003
HapB1 9.3 0.01
HapB4 7.83 0.02
HapC5 6.11 0.047
KCNJ6 rs860795 C 1.47 0.481
rs857967 A 3.9 0.142
rs858010 A 3.93 0.14
rs858003 T 3.65 0.161
rs2835914 C 0.02 0.99
rs858035 C 3.03 0.22
rs2835925 G 12.62 0.002 A
HapB2 3.9 0.142
HapC3 3.93 0.14
HapE2 6.39 0.041
HapE7 13.18 0.001
KCNK3 rs1662988 T FE 0.023 R
rs7584568 A FE 0.004 D
HapB1 9.92 0.007
HapB4 6.27 0.043
KCNK9 rs2542424 G 0.74 0.69 A
rs2014712 T FE 0.041 R
rs2545457 C 3.71 0.156 A
rs888349 C 3.14 0.208 A
Thomazeau 2016 COMT rs4680 A: 83.3% vs 63.5% - 0.047 patient characteristics (gender, high school diploma, physical activity), pain intensity and consequences, Pain Matcher, anesthetic procedure; no ancestry
OPRM1 rs1799971 G: 16.7% vs 17.6% - - - 0.912
COMT Rs4680 A 3.42 0.93 12.51 0.63 D
George 2016 ADRB2 rs1042713 R2 increment 0.863 NR age, sex, race, and preoperative status, and psychological factors, and interactions; no ancestry
A 0.001
AVPR1A rs1042615 C 0.01 0.338
TNF/LTA rs2229094 C 0.009 0.368
IL6 rs1800797 A 0.002 0.793
IL6 rs2069840 C 0.001 0.867
Kalliomaki 2016 TNF-α rs1800629 GG (78% vs 58.8%) 1.93* 1.03 3.61 0.036 R NR. No ancestry
CACNA2D2 rs5030977 GG (72.3% vs 70.2%) 1.14* 0.66 2 0.603 R
GRIK rs6691840 TT (59.6% vs 51.8%) 1.16* 0.7 1.92 0.247 R
BDNF rs6265 GG (63.8% vs 62.3%) 0.96* 0.58 1.61 0.34 R
OPRM1 rs1799971 AA (70.2% vs 70.2%) 0.98* 0.57 1.68 0.935 R
Warner 2017 PRKCA rs887797 A 2 1.48 2.7 4.29×10−6 Unadjusted
CDH18 rs4866176 A 2.86 1.76 4.66 1.19×10−5
TG rs1133076 A 1.66 1.23 2.24 3.41×10−4
MAT2B Rs7734804 A 4.64 2.26 9.53 5.25 × 10−6
GPD2 Rs298235 A 6.72 2.67 16.92 3.41 × 10−6
FOXL1 Rs12596162 A 2.05 1.51 2.79 3.53 × 10−6
Meta-analysis
PRKCA Rs887797 A 1.48 1.23 1.75 1.65 × 10−5 A
PRKCA Rs887797 A 2.41 1.74 3.34 1.29 × 10−7 R

Values are provided if reported in the study or deducible from the information provided in the study.

*

RR: Relative risk; FE: Fisher’s Exact

^

X2: chi-square test

OR: Odds ratio; CI: confidence interval; LL: lower limit; UL: upper limit; NR: Not reported; NS: Not significant, Gene names are reported in Table 1. Genetic model A: Additive, D: Dominant; R: Recessive.

Bolded p-values represent nominal significance (0.05) for CPSP variant association

Studies included in the meta-analysis are shaded in gray color.