TIMP3 Gene Polymorphisms of -1296 T > C and -915 A > G Increase the Susceptibility to Arsenic-Induced Skin Cancer: A Cohort Study and In Silico Analysis of Mutation Impacts
Abstract
:1. Introduction
2. Results
2.1. Baseline Characteristics by TIMP3 Promoter Genotypes
2.2. Factors Associated with the Skin Cancer Incidence
2.3. Synergetic Effect of the TIMP3 Genotype and Arsenic Exposure
2.4. TIMP3 Genotype and Incidence of Skin Lesions
2.5. In Silico Analysis of TF-Binding Sites (TFBSs) and the Impacts of Mutations
3. Discussion
4. Materials and Methods
4.1. Study Participants and Questionnaire Data
4.2. Identification of Skin Cancer Cases
4.3. Identification of Skin Lesion Cases
4.4. TIMP3 Promoter Genotyping
4.5. In Silico Analysis of TF-Binding Profiles
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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rs9619311 (N = 1078) | rs2234921 (N = 1072) | |||||||
---|---|---|---|---|---|---|---|---|
Variables * | T/T (n = 911) † | T/C (n = 156) | C/C (n = 11) | p | A/A (n = 909) | A/G (n = 157) | G/G (n = 6) | p |
Age at enrollment, years | 0.130 | 0.104 | ||||||
30~50 | 290 (31.8) | 35 (22.4) | 2 (18.2) | 292 (32.1) | 35 (22.3) | 1 (16.7) | ||
50~60 | 301 (33.0) | 55 (35.3) | 4 (36.4) | 299 (32.9) | 58 (36.9) | 2 (33.3) | ||
≥60 | 320 (35.1) | 66 (42.3) | 5 (45.5) | 318 (35.0) | 64 (40.8) | 3 (50.0) | ||
Gender | 0.356 | 0.670 | ||||||
Female | 506 (55.5) | 82 (52.6) | 4 (36.4) | 504 (55.5) | 82 (52.2) | 4 (66.7) | ||
Male | 405 (44.5) | 74 (47.4) | 7 (63.6) | 405 (44.6) | 75 (47.8) | 2 (33.3) | ||
Education level | 0.427 | 0.117 | ||||||
No schooling | 337 (37.0) | 53 (34.0) | 6 (54.6) | 337 (37.1) | 50 (31.9) | 4 (66.7) | ||
Elementary | 438 (48.1) | 85 (54.5) | 4 (36.4) | 435 (47.9) | 90 (57.3) | 2 (33.3) | ||
Junior high or above | 136 (14.9) | 18 (11.5) | 1 (9.1) | 137 (15.1) | 17 (10.8) | 0 (00.0) | ||
Cigarette smoking | 0.290 | 0.584 | ||||||
No | 657 (72.1) | 118 (75.6) | 10 (90.9) | 657 (72.3) | 119 (75.8) | 4 (66.7) | ||
Yes | 254 (27.9) | 38 (24.4) | 1 (9.1) | 252 (27.7) | 38 (24.2) | 2 (33.3) | ||
Alcohol consumption | 0.645 | 0.553 | ||||||
No | 773 (84.9) | 137 (87.8) | 10 (90.9) | 771 (84.8) | 137 (87.3) | 6 (100.0) | ||
Yes | 138 (15.2) | 19 (12.2) | 1 (9.1) | 138 (15.2) | 20 (12.7) | 0 (0.00) | ||
Body-mass index, kg/m2 | 0.561 | 0.069 | ||||||
≤23 | 319 (35.4) | 63 (40.9) | 5 (45.5) | 318 (35.4) | 66 (42.6) | 2 (33.3) | ||
23~27 | 388 (43.1) | 64 (41.6) | 5 (45.5) | 387 (43.1) | 66 (42.6) | 1 (16.7) | ||
≥27 | 194 (21.5) | 27 (17.5) | 1 (9.1) | 194 (21.6) | 23 (14.8) | 3 (50.0) | ||
Arsenic exposure, ppm-years | 0.285 | 0.888 | ||||||
≤7.7 | 381 (48.6) | 74 (56.9) | 4 (44.4) | 381 (48.7) | 67 (51.9) | 4 (66.7) | ||
7.7~17.5 | 201 (25.6) | 29 (22.3) | 4 (44.4) | 200 (25.6) | 33 (25.6) | 1 (16.7) | ||
>17.5 | 202 (25.8) | 27 (20.8) | 1 (11.1) | 201 (25.7) | 29 (22.5) | 1 (16.7) |
Age- and Gender-Adjusted | Multivariate-Adjusted * | |||||
---|---|---|---|---|---|---|
Characteristic | P-Y | SC Cases | HR (95% CI) | p | HR (95% CI) | p |
Age | 20,551 | 50 | 1.05 (1.02~1.08) | <0.001 | 1.05 (1.02~1.08) | 0.004 |
Gender | ||||||
Female | 11,782 | 22 | 1.00 | |||
Male | 8769 | 28 | 1.67 (0.95~2.92) | 0.073 | 4.09 (2.09~8.03) | <0.001 |
Education level | ||||||
No schooling | 7040 | 25 | 1.00 | |||
Elementary or above | 13,495 | 25 | 0.51 (0.28~0.95) | 0.033 | 0.49 (0.26~0.92) | 0.025 |
Smoking | ||||||
No | 15,598 | 45 | 1.00 | |||
Yes | 4952 | 5 | 0.13 (0.05~0.34) | <0.001 | 0.18 (0.07~0.48) | <0.001 |
Drinking | ||||||
No | 17,816 | 46 | 1.00 | |||
Yes | 2735 | 4 | 0.34 (0.12~0.98) | 0.046 | 0.51 (0.17~1.49) | 0.216 |
Body-mass index, kg/m2 | ||||||
<27 | 16,179 | 39 | ||||
≥27 | 4179 | 11 | 1.12 (0.57~2.20) | 0.736 | (N.A.) | |
Arsenic exposure, ppm-years | ||||||
≤7.7 | 8077 | 9 | 1.00 | 1.00 | ||
7.7~17.5 | 4897 | 14 | 2.64 (1.13~6.17) | 0.026 | 2.12 (0.90~5.01) | 0.088 |
>17.5 | 4166 | 23 | 4.18 (1.92~9.10) | <0.001 | 3.17 (1.44~6.99) | 0.004 |
Trend test | 1.98 (1.38~2.84) | <0.001 | 1.74 (1.20~2.52) | 0.004 |
TIMP3 Genotype | P-Y | SC Cases | aHR (95% CI) * | p |
---|---|---|---|---|
rs9619311(T > C) | ||||
Additive model | ||||
T/T | 13,695 | 34 | 1.00 | 0.606 |
T/C | 2064 | 7 | 1.25 (0.54~2.87) | |
C/C | 114 | 0 | (N.A.) | |
Dominant model | ||||
T/T | 13,695 | 34 | 1.00 | |
T/C + C/C | 2178 | 7 | 1.16 (0.51~2.68) | 0.722 |
Recessive model | ||||
T/T + T/C | 15,759 | 41 | 1.00 | |
C/C | 114 | 0 | (N.A.) | |
rs2234921(A > G) | ||||
Additive model | ||||
A/A | 13,665 | 33 | 1.00 | |
A/G | 2050 | 7 | 1.29 (0.56~2.96) | 0.551 |
G/G | 84 | 1 | 6.71 (0.85~53.20) | 0.071 |
Dominant model | ||||
A/A | 13,665 | 33 | 1.00 | |
A/G + G/G | 2134 | 8 | 1.43 (0.65~3.16) | 0.372 |
Recessive model | ||||
A/A + A/G | 15,715 | 40 | 1.00 | |
G/G | 84 | 1 | 6.42 (0.81~50.71) | 0.078 |
TIMP3 Genotype | Arsenic Exposure * | Cases/P-Y | aHR (95% CI) † | p |
---|---|---|---|---|
rs9619311 | ||||
Dominant | ||||
T/T | Low | 7/6420 | 1.00 | |
High | 27/7274 | 2.35 (1.00~5.53) | 0.051 | |
T/C + C/C | Low | 1/1205 | 0.52 (0.06~4.27) | 0.542 |
High | 6/973 | 3.29 (1.07~10.12) | 0.038 | |
Trend test | 1.82 (1.06~3.13) | 0.030 | ||
Multiplicative test | 1.41 (0.57~3.46) | 0.455 | ||
rs2234921 | ||||
Dominant | ||||
A/A | Low | 7/6412 | 1.00 | |
High | 26/7253 | 2.26 (0.96~5.34) | 0.063 | |
A/G + G/G | Low | 1/1124 | 0.64 (0.08~5.28) | 0.682 |
High | 7/1010 | 3.81 (1.30~11.23) | 0.015 | |
Trend test | 1.95 (1.14~3.32) | 0.015 | ||
Multiplicative test | 1.69 (0.72~3.95) | 0.226 | ||
Recessive | ||||
A/A + A/G | Low | 8/7481 | 1.00 | |
High | 32/8234 | 2.52 (1.13~5.62) | 0.024 | |
G/G | Low | 0/54 | N.A. | |
High | 1/30 | 82.52 (8.60~791.61) | <0.001 | |
Trend test | 2.98 (1.31~6.77) | 0.009 | ||
Multiplicative test | 32.50 (3.68~286.77) | 0.002 | ||
Haplotype block | ||||
Dominant | ||||
T-A/T-A | Low | 7/6380 | 1.00 | |
High | 26/7228 | 2.16 (0.92~5.12) | 0.079 | |
T-A/C-G + C-G/C-G | Low | 1/1030 | 0.71 (0.09~5.82) | 0.750 |
High | 6/929 | 3.31 (1.08~10.18) | 0.037 | |
Trend test | 1.82 (1.05~3.14) | 0.032 | ||
Multiplicative test | 1.53 (0.62~3.78) | 0.354 |
TIMP3 Genotype | P-Y | Hyperkeratosis | aHR (95% CI) * | p | P-Y | Hyperpigmentation | aHR (95% CI) | p |
---|---|---|---|---|---|---|---|---|
rs9619311(T > C) | ||||||||
Additive model | ||||||||
T/T | 3707 | 52 | 1.00 | 3246 | 94 | 1.00 | ||
T/C | 391 | 10 | 1.93 (0.96~3.89) | 0.064 | 381 | 11 | 0.90 (0.48~1.70) | 0.752 |
C/C | 27 | 0 | (N.A.) | 14 | 2 | 3.51 (0.82~14.96) | 0.090 | |
Dominant model | ||||||||
T/T | 3707 | 52 | 1.00 | 3246 | 94 | 1.00 | ||
T/C + C/C | 419 | 10 | 1.75 (0.87~3.52) | 0.116 | 395 | 13 | 1.02 (0.56~1.83) | 0.962 |
Recessive model | ||||||||
T/T + T/C | 4098 | 62 | 1.00 | 3627 | 105 | 1.00 | ||
C/C | 27 | 0 | (N.A.) | 14 | 2 | 3.56 (0.84~15.15) | 0.086 | |
rs2234921(A > G) | ||||||||
Additive model | ||||||||
A/A | 3683 | 51 | 1.00 | 3222 | 93 | 1.00 | ||
A/G | 431 | 10 | 1.76 (0.87~3.55) | 0.115 | 408 | 12 | 0.92 (0.50~28.31) | 0.795 |
G/G | 11 | 1 | 7.13 (0.94~53.81) | 0.057 | 11 | 2 | 6.69 (1.58~28.31) | 0.010 |
Dominant model | ||||||||
A/A | 3683 | 51 | 1.00 | 3222 | 93 | 1.00 | ||
A/G + G/G | 443 | 11 | 1.91 (0.98~3.76) | 0.059 | 420 | 14 | 1.07 (0.60~1.89) | 0.826 |
Recessive model | ||||||||
A/A + A/G | 4114 | 61 | 1.00 | 3630 | 105 | 1.00 | ||
G/G | 11 | 1 | 6.94 (0.92~52.40) | 0.060 | 11 | 2 | 6.72 (1.59~28.42) | 0.010 |
TIMP3 Genotype | Arsenic Exposure * | Keratosis/P-Y | aHR (95% CI) † | p | Pigmentation/P-Y | aHR (95% CI) | p |
---|---|---|---|---|---|---|---|
rs9619311 | |||||||
Dominant | |||||||
T/T | Low | 8/1291 | 1.00 | 12/1300 | 1.00 | ||
High | 44/2416 | 2.48 (1.06~5.78) | 0.036 | 82/1945 | 2.89 (1.51~5.54) | 0.001 | |
T/C + C/C | Low | 3/189 | 2.63 (0.67~10.24) | 0.164 | 2/176 | 1.09 (0.24~4.93) | 0.913 |
High | 7/229 | 3.81 (1.24~11.70) | 0.020 | 11/219 | 2.81 (1.17~6.71) | 0.021 | |
Trend test | 1.94 (1.16~3.26) | 0.012 | Trend test | 1.65 (1.14~2.39) | 0.008 | ||
Multiplicative test | 1.53 (0.68~3.47) | 0.308 | Multiplicative test | 0.97 (0.51~1.84) | 0.924 | ||
rs2234921 | |||||||
Dominant | |||||||
A/A | Low | 8/1278 | 1.00 | 12/1280 | 1.00 | ||
High | 43/2405 | 2.43 (1.04~5.68) | 0.041 | 81/1941 | 2.82 (1.46~5.41) | 0.002 | |
A/G + G/G | Low | 3/209 | 2.46 (0.63~9.65) | 0.196 | 2/196 | 0.97 (0.21~4.41) | 0.967 |
High | 8/234 | 4.30 (1.44~12.82) | 0.009 | 12/223 | 2.96 (1.25~6.96) | 0.013 | |
Trend test | 2.05 (1.22~3.44) | 0.007 | Trend test | 1.68 (1.16~2.42) | 0.006 | ||
Multiplicative test | 1.76 (0.81~3.83) | 0.151 | Multiplicative test | 1.05 (0.57~1.94) | 0.878 | ||
Recessive | |||||||
A/A + A/G | Low | 11/1480 | 1.00 | 14/1477 | 1.00 | ||
High | 50/2634 | 2.02 (0.97~4.22) | 0.061 | 91/2153 | 2.77 (1.51~5.06) | 0.001 | |
G/G | Low | 0/0 | N.A. | 0/0 | N.A. | ||
High | 1/11 | 14.05 (1.74~113.70) | 0.013 | 2/11 | 19.82 (4.34~90.57) | <0.001 | |
Trend test | 2.27 (1.10~4.69) | 0.027 | Trend test | 3.12 (1.73~5.64) | <0.001 | ||
Multiplicative test | 6.95 (0.92~52.41) | 0.060 | Multiplicative test | 7.17 (1.70~30.23) | 0.007 |
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Wu, M.-M.; Chen, C.-W.; Chen, C.-Y.; Lee, C.-H.; Chou, M.; Hsu, L.-I.; Lee, T.-C.; Chen, C.-J. TIMP3 Gene Polymorphisms of -1296 T > C and -915 A > G Increase the Susceptibility to Arsenic-Induced Skin Cancer: A Cohort Study and In Silico Analysis of Mutation Impacts. Int. J. Mol. Sci. 2022, 23, 14980. https://doi.org/10.3390/ijms232314980
Wu M-M, Chen C-W, Chen C-Y, Lee C-H, Chou M, Hsu L-I, Lee T-C, Chen C-J. TIMP3 Gene Polymorphisms of -1296 T > C and -915 A > G Increase the Susceptibility to Arsenic-Induced Skin Cancer: A Cohort Study and In Silico Analysis of Mutation Impacts. International Journal of Molecular Sciences. 2022; 23(23):14980. https://doi.org/10.3390/ijms232314980
Chicago/Turabian StyleWu, Meei-Maan, Chi-Wei Chen, Chiu-Yi Chen, Chih-Hung Lee, Mark Chou, Ling-I Hsu, Te-Chang Lee, and Chien-Jen Chen. 2022. "TIMP3 Gene Polymorphisms of -1296 T > C and -915 A > G Increase the Susceptibility to Arsenic-Induced Skin Cancer: A Cohort Study and In Silico Analysis of Mutation Impacts" International Journal of Molecular Sciences 23, no. 23: 14980. https://doi.org/10.3390/ijms232314980