Background
Methods
Study participants
Characteristics | Cases | Control | P value |
---|---|---|---|
Number | 566 | 578 | |
Age (mean ± SD) | 50.91 ± 11.23 | 49.22 ± 10.11 | 0.017 |
smoking and drink | |||
No | 328 | ||
Yes | 40 | ||
Age of menarche | |||
≤14 | 145 | ||
>14 | 119 | ||
Menopausal status | |||
Premenopausal | 104 | ||
Postmenopausal | 156 | ||
Procreative times | |||
<1 | 104 | ||
≥1 | 130 | ||
Tumor size | |||
<2 cm | 105 | ||
≥2 cm | 154 | ||
Tumor site | |||
left | 256 | ||
right | 241 | ||
Lymph node involvement | |||
Negative | 201 | ||
Positive | 197 | ||
Clinical stage | |||
III-IV | 114 | ||
I- II | 272 | ||
Immunohistochemistry results | |||
ER (−) | 108 | ||
ER (+) | 208 | ||
PR (−) | 145 | ||
PR (+) | 166 | ||
c-erb(−) | 91 | ||
c-erb(+) | 214 |
SNP selection and genotyping
Bioinformatics and expression analyses
Statistical analysis
Results
SNP | Gene | Allele | RegulomeDB | HaploReg |
---|---|---|---|---|
rs2277698 (synonymous) |
TIMP-2
| T/C | No Data | SiPhy conse, Selected eQTL hits |
rs2009196 (intronic) |
TIMP-2
| C/G | 5 | DNase, Motifs changed, Selected eQTL hits |
rs7342880 (intronic) |
TIMP-2
| A/C | 5 | DNase, Motifs changed, Selected eQTL hits |
rs11654470 (intronic) |
TIMP-2
| C/T | 5 | DNase, Motifs changed, Selected eQTL hits |
rs2003241 (intronic) |
TIMP-2
| C/T | 3a | DNase, Motifs changed, Selected eQTL hits |
rs4789936 (5′-UTR) |
TIMP-2
| T/C | 2b | Motifs changed, Selected eQTL hits |
SNP | Gene | chromosome | Position | Allele | Minor allele frequency | HWE p value | OR (95%CI) |
p
| |
---|---|---|---|---|---|---|---|---|---|
Case | Control | ||||||||
rs2277698 |
TIMP-2
| 17q25.3 | 76,867,017 | T/C | 0.201 | 0.236 | 0.0651 | 0.81(0.67–0.99) | 0.041* |
rs2009196 |
TIMP-2
| 17q25.3 | 76,870,581 | C/G | 0.392 | 0.426 | 0.3502 | 0.87(0.74–1.03) | 0.099 |
rs7342880 |
TIMP-2
| 17q25.3 | 76,874,512 | A/C | 0.161 | 0.150 | 0.7433 | 1.09(0.87–1.37) | 0.448 |
rs11654470 |
TIMP-2
| 17q25.3 | 76,877,331 | C/T | 0.23 | 0.273 | 0.0119* | 0.80(0.66–0.96) | 0.019 |
rs2003241 |
TIMP-2
| 17q25.3 | 76,885,117 | C/T | 0.164 | 0.161 | 0.0196* | 1.02(0.82–1.28) | 0.853 |
rs4789936 |
TIMP-2
| 17q25.3 | 76,897,974 | T/C | 0.299 | 0.307 | 0.6256 | 0.96(0.80–1.15) | 0.658 |
SNP | Model | Genotype | Control | Case | OR (95%CI) |
p
|
---|---|---|---|---|---|---|
rs2277698 | Co-dominant | CC | 329 (56.9%) | 361 (63.3%) | 1 | 0.080 |
CT | 225 (38.9%) | 189 (33.2%) | 0.77 (0.60–0.98) | |||
TT | 24 (4.2%) | 20 (3.5%) | 0.72 (0.39–1.33) | |||
Dominant | CC | 329 (56.9%) | 361 (63.3%) | 1 | 0.025* | |
CT + TT | 249 (43.1%) | 209 (36.7%) | 0.76 (0.60–0.97) | |||
Recessive | CC + CT | 554 (95.8%) | 550 (96.5%) | 1 | 0.460 | |
TT | 24 (4.2%) | 20 (3.5%) | 0.80 (0.43–1.46) | |||
Log-additive | – | – | – | 0.80 (0.65–0.98) | 0.029* | |
rs2009196 | Co-dominant | GG | 184 (31.9%) | 202 (35.4%) | 1 | 0.190 |
CG | 293 (50.9%) | 290 (50.8%) | 0.90 (0.69–1.16) | |||
CC | 99 (17.2%) | 79 (13.8%) | 0.72 (0.50–1.03) | |||
Dominant | GG | 184 (31.9%) | 202 (35.4%) | 1 | 0.210 | |
CG + CC | 392 (68.1%) | 369 (64.6%) | 0.85 (0.67–1.09) | |||
Recessive | GG + CG | 477 (82.8%) | 492 (86.2%) | 1 | 0.100 | |
C/C | 99 (17.2%) | 79 (13.8%) | 0.76 (0.55–1.05) | |||
Log-additive | – | – | – | 0.86 (0.72–1.02) | 0.078 | |
rs7342880 | Co-dominant | CC | 419 (72.5%) | 399 (69.9%) | 1 | 0.470 |
AC | 145 (25.1%) | 160 (28.0%) | 1.17 (0.90–1.52) | |||
AA | 14 (2.4%) | 12 (2.1%) | 0.90 (0.41–1.97) | |||
Dominant | CC | 419 (72.5%) | 399 (69.9%) | 1 | 0.300 | |
AC + AA | 159 (27.5%) | 172 (30.1%) | 1.15 (0.89–1.48) | |||
Recessive | CC + AC | 564 (97.6) | 559 (97.9) | 1 | 0.710 | |
AA | 14 (2.4%) | 12 (2.1%) | 0.86 (0.39–1.88) | |||
Log-additive | – | – | – | 1.10 (0.88–1.38) | 0.410 | |
rs4789936 | Co-dominant | CC | 280 (48.4%) | 280 (49.0%) | 1 | 0.850 |
AC | 241 (41.7%) | 241 (42.2%) | 1.00 (0.78–1.27) | |||
AA | 57 (9.9%) | 50 (8.8%) | 0.89 (0.59–1.35) | |||
Dominant | CC | 280 (48.4%) | 280 (49.0%) | 1 | 0.840 | |
AC + AA | 298 (90.1%) | 291 (51.0%) | 0.98 (0.77–1.23) | |||
Recessive | CC + AC | 521 (90.1%) | 521 (91.2%) | 1 | 0.560 | |
AA | 57 (9.9%) | 50 (8.8%) | 0.89 (0.60–1.33) | |||
Log-additive | – | – | – | 0.96 (0.81–1.15) | 0.680 |
Variants | CC/TC/TT | Allele model | Genotype model | Dominant model | Recessive model | Additive model | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OR (95%CI) |
p
| TC genotype OR (95%CI) |
p
| TT genotype OR (95%CI) |
p
| OR (95%CI) |
p
| OR (95%CI) |
p
| OR (95%CI) |
p
| ||
c-erb | |||||||||||||
Negative | 126/76/11 | 1 | |||||||||||
Positive | 66/23/2 | 1.72(1.08–2.74) | 0.022 | 1.78(1.02–3.1) | 0.043 | 2.88(0.62–13.4) | 0.178 | 1.87(1.09–3.2) | 0.023 | 2.4(0.52–11.08) | 0.261 | 1.75(1.09–2.82) | 0.021 |
ER | |||||||||||||
Negative | 76/28/4 | 1 | |||||||||||
Positive | 124/74/9 | 1.43(0.93–2.19) | 0.1 | 1.63(0.96–2.75) | 0.069 | 1.38(0.41–4.63) | 0.604 | 1.6(0.97–2.63) | 0.068 | 1.18(0.36–3.94) | 0.784 | 1.43(0.93–2.2) | 0.102 |
PR | |||||||||||||
Negative | 102/39/4 | 1 | |||||||||||
Positive | 95/61/9 | 1.63(1.09–2.43) | 0.017 | 1.66(1.01–2.71) | 0.045 | 2.42(0.72–8.14) | 0.152 | 1.73(1.08–2.78) | 0.024 | 2.06(0.62–6.85) | 0.239 | 1.62(1.08–2.43) | 0.021 |
Clinical stage | |||||||||||||
I- II | 175/86/11 | 1 | |||||||||||
III-IV | 71/38/4 | 1.03(0.7–1.52) | 0.874 | 1.09(0.5–2.35) | 0.83 | 0.55(0.08–3.84) | 0.542 | 1.01(0.48–2.13) | 0.973 | 0.53(0.08–3.65) | 0.518 | 0.94(0.5–1.76) | 0.843 |
Menopausal status | |||||||||||||
Premenopausal | 64/34/6 | 1 | |||||||||||
Postmenopausal | 99/51/6 | 0.89(0.58–1.37) | 0.598 | 1.09(0.5–2.35) | 0.83 | 0.55(0.08–3.84) | 0.542 | 1.01(0.48–2.13) | 0.973 | 0.53(0.08–3.65) | 0.518 | 0.94(0.5–1.76) | 0.843 |
Lymph node involvement | |||||||||||||
Negative | 129/64/8 | 1 | |||||||||||
Positive | 127/61/7 | 0.96(0.67–1.36) | 0.812 | 0.96(0.63–1.48) | 0.861 | 0.9(0.32–2.55) | 0.837 | 0.95(0.63–1.44) | 0.827 | 0.91(0.32–2.56) | 0.854 | 0.96(0.67–1.36) | 0.803 |
≤49 | |||||||||||||
control | 153/117/16 | 1 | |||||||||||
case | 199/98/11 | 0.69(0.52–0.9) | 0.007 | 0.66(0.47–0.93) | 0.017 | 0.5(0.23–1.13) | 0.095 | 0.64(0.46–0.89) | 0.008 | 0.59(0.27–1.31) | 0.193 | 0.68(0.51–0.9) | 0.007 |
>49 | |||||||||||||
control | 176/108/8 | 1 | |||||||||||
case | 161/88/8 | 0.94(0.7–1.26) | 0.684 | 0.89(0.62–1.27) | 0.516 | 1.1(0.4–3) | 0.852 | 0.9(0.64–1.28) | 0.566 | 1.15(0.42–3.11) | 0.785 | 0.94(0.69–1.27) | 0.67 |
Procreative times | |||||||||||||
≥1 | 79/43/8 | 1 | |||||||||||
<1 | 64/37/3 | 0.89(0.57–1.38) | 0.599 | 1.05(0.6–1.83) | 0.869 | 0.48(0.12–1.93) | 0.3 | 0.96(0.56–1.65) | 0.889 | 0.47(0.12–1.87) | 0.283 | 0.89(0.56–1.4) | 0.611 |
Age of menarche | |||||||||||||
>14 | 71/43/5 | 1 | |||||||||||
≤14 | 93/45/7 | 0.89(0.59–1.36) | 0.591 | 0.79 (0.47–1.33) | 0.372 | 1.11(0.33–3.66) | 0.868 | 0.82(0.5–1.36) | 0.441 | 1.2(0.37–3.92) | 0.76 | 0.89(0.59–1.36) | 0.592 |
Tumor size | |||||||||||||
≥2 cm | 70/31/4 | 1 | |||||||||||
<2 cm | 90/56/8 | 1.34(0.86–2.07) | 0.191 | 1.44(0.84–2.48) | 0.189 | 1.5(0.43–5.25) | 0.529 | 1.45(0.86–2.44) | 0.166 | 1.32(0.38–4.56) | 0.661 | 1.35(0.86–2.1) | 0.188 |
SNP | Haplotype | Freq | OR (95%CI) |
p
|
---|---|---|---|---|
rs2277698|rs2009196 |rs7342880 | CGC | 0.591 | 1 | |
TCC | 0.218 | 0.79 (0.63–0.97) | 0.028* | |
CCA | 0.155 | 1.03 (0.81–1.30) | 0.830 | |
CCC | 0.036 | 0.64 (0.41–1.02) | 0.059 |