The Variations’ in Genes Encoding TIM-3 and Its Ligand, Galectin-9, Influence on ccRCC Risk and Prognosis
Abstract
:1. Introduction
2. Results
2.1. Association between TIM-3 and LGALS9 SNPs and Susceptibility to ccRCC
2.2. Association of TIM-3 and LGALS9 Polymorphisms with Clinical Features of ccRCC Patients
2.3. Haplotype Analysis
2.4. TIM-3 and LGALS9 Gene Polymorphisms in Relation to Overall Survival
2.5. Univariate and Multivariate Analysis of Risk Factors Influencing ccRCC Risk and Overall Patient Survival
3. Discussion
4. Conclusions
5. Materials and Methods
5.1. ccRCC Patients
5.2. Controls
5.3. SNP Selection
5.4. DNA Isolation and SNP Genotyping
5.5. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cases | Controls | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
SNP | Genotype | Allele | N | % | N | % | OR | 95% CI | p-Value | |
rs1036199 | ||||||||||
AA | 149 | 62.87 | 256 | 62.44 | 1 | 0.377 | ||||
AC | 83 | 35.02 | 137 | 33.41 | 1.042 | 0.743 | 1.462 | |||
CC | 5 | 2.11 | 17 | 4.15 | 0.539 | 0.203 | 1.435 | |||
AC + CC | 88 | 37.13 | 154 | 37.56 | 0.983 | 0.707 | 1.367 | 0.913 | ||
AA + AC | 232 | 97.89 | 393 | 95.85 | 1.880 | 0.711 | 4.968 | 0.169 | ||
A | 381 | 80.38 | 649 | 79.15 | 1 | |||||
C | 93 | 19.62 | 171 | 20.85 | 0.928 | 0.700 | 1.230 | 0.596 | ||
rs10057302 | ||||||||||
CC | 228 | 96.20 | 376 | 91.71 | 1 | 0.071 | ||||
AC | 9 | 3.80 | 32 | 7.80 | 0.482 | 0.229 | 1.011 | |||
AA | 0 | 0.00 | 2 | 0.49 | 0.330 | 0.016 | 6.895 | |||
AC + AA | 9 | 3.80 | 34 | 8.29 | 0.454 | 0.217 | 0.948 | 0.027 | ||
CC + AC | 237 | 100.00 | 408 | 99.51 | 2.907 | 0.139 | 60.809 | 0.282 | ||
C | 465 | 98.10 | 784 | 95.61 | 2 | |||||
A | 9 | 1.90 | 36 | 4.39 | 0.439 | 0.213 | 0.904 | 0.018 | ||
rs3751093 | ||||||||||
GG | 128 | 54.47 | 242 | 59.02 | 1 | 0.142 | ||||
AG | 86 | 36.60 | 147 | 35.85 | 1.107 | 0.787 | 1.556 | |||
AA | 21 | 8.94 | 21 | 5.12 | 1.887 | 1.000 | 3.561 | |||
AG + AA | 107 | 45.53 | 168 | 40.98 | 1.204 | 0.872 | 1.663 | 0.261 | ||
GG + AG | 214 | 91.06 | 389 | 94.88 | 0.551 | 0.296 | 1.024 | 0.059 | ||
G | 342 | 72.77 | 631 | 76.95 | 1 | |||||
A | 128 | 27.23 | 189 | 23.05 | 1.250 | 0.964 | 1.621 | 0.093 | ||
rs361497 | ||||||||||
GG | 120 | 51.06 | 225 | 55.42 | 1 | 0.220 | ||||
AG | 93 | 39.57 | 157 | 38.67 | 1.111 | 0.792 | 1.558 | |||
AA | 22 | 9.36 | 24 | 5.91 | 1.719 | 0.930 | 3.174 | |||
AG + AA | 115 | 48.94 | 181 | 44.58 | 1.191 | 0.863 | 1.642 | 0.287 | ||
GG + AG | 213 | 90.64 | 382 | 94.09 | 0.608 | 0.335 | 1.103 | 0.103 | ||
G | 333 | 70.85 | 607 | 74.75 | 1 | |||||
A | 137 | 29.15 | 205 | 25.25 | 1.219 | 0.946 | 1.571 | 0.128 | ||
rs4239242 | ||||||||||
TT | 91 | 38.56 | 177 | 43.17 | 1 | 0.307 | ||||
CT | 104 | 44.07 | 178 | 43.41 | 1.136 | 0.801 | 1.610 | |||
CC | 41 | 17.37 | 55 | 13.41 | 1.451 | 0.902 | 2.332 | |||
CT + CC | 145 | 61.44 | 233 | 56.83 | 1.209 | 0.872 | 1.675 | 0.252 | ||
TT + CT | 195 | 82.63 | 355 | 86.59 | 0.735 | 0.474 | 1.140 | 0.174 | ||
T | 286 | 60.59 | 532 | 64.88 | 1 | |||||
C | 186 | 39.41 | 288 | 35.12 | 1.202 | 0.951 | 1.518 | 0.124 | ||
rs4794976 | ||||||||||
TT | 110 | 46.61 | 210 | 51.22 | 1 | 0.049 | ||||
GT | 92 | 38.98 | 166 | 40.49 | 1.058 | 0.751 | 1.491 | |||
GG | 34 | 14.41 | 34 | 8.29 | 1.905 | 1.127 | 3.221 | |||
GT + GG | 126 | 53.39 | 200 | 48.78 | 1.202 | 0.873 | 1.656 | 0.260 | ||
TT + GT | 202 | 85.59 | 376 | 91.71 | 0.538 | 0.326 | 0.888 | 0.015 | ||
T | 312 | 66.10 | 586 | 71.46 | 1 | |||||
G | 160 | 33.90 | 234 | 28.54 | 1.285 | 1.007 | 1.638 | 0.044 |
Cases | Controls | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
SNP | Genotype | Allele | N | % | N | % | OR | 95% CI | p-Value | |
rs1036199 | ||||||||||
AA | 58 | 67.44 | 91 | 61.49 | 1 | 0.191 | ||||
AC | 28 | 32.56 | 52 | 35.14 | 0.849 | 0.484 | 1.489 | |||
CC | 0 | 0.00 | 5 | 3.38 | 0.142 | 0.008 | 2.620 | |||
AC + CC | 28 | 32.56 | 57 | 38.51 | 0.775 | 0.445 | 1.352 | 0.362 | ||
AA + AC | 86 | 100.00 | 143 | 96.62 | - | - | - | - | ||
A | 144 | 83.72 | 234 | 79.05 | 1 | |||||
C | 28 | 16.28 | 62 | 20.95 | 0.740 | 0.454 | 1.207 | 0.217 | ||
rs10057302 | ||||||||||
CC | 83 | 96.51 | 134 | 90.54 | 1 | - | ||||
AC | 3 | 3.49 | 14 | 9.46 | 0.389 | 0.117 | 1.289 | |||
AA | 0 | 0.00 | 0 | 0.00 | - | - | - | |||
AC + AA | 3 | 3.49 | 14 | 9.46 | 0.389 | 0.117 | 1.289 | 0.090 | ||
CC + AC | 86 | 100.00 | 148 | 100.00 | - | - | - | - | ||
C | 169 | 98.26 | 282 | 95.27 | 1 | |||||
A | 3 | 1.74 | 14 | 4.73 | 0.402 | 0.123 | 1.313 | 0.096 | ||
rs3751093 | ||||||||||
GG | 41 | 48.24 | 90 | 60.81 | 1 | 0.137 | ||||
AG | 34 | 40.00 | 48 | 32.43 | 1.551 | 0.877 | 2.745 | |||
AA | 10 | 11.76 | 10 | 6.76 | 2.181 | 0.860 | 5.533 | |||
AG + AA | 44 | 51.76 | 58 | 39.19 | 1.659 | 0.971 | 2.834 | 0.063 | ||
GG + AG | 75 | 88.24 | 138 | 93.24 | 0.545 | 0.222 | 1.341 | 0.190 | ||
G | 116 | 68.24 | 228 | 77.03 | 1 | |||||
A | 54 | 31.76 | 68 | 22.97 | 1.561 | 1.025 | 2.375 | 0.038 | ||
rs361497 | ||||||||||
GG | 39 | 45.88 | 85 | 57.43 | 1 | 0.132 | ||||
AG | 35 | 41.18 | 53 | 35.81 | 1.436 | 0.814 | 2.534 | |||
AA | 11 | 12.94 | 10 | 6.76 | 2.371 | 0.947 | 5.935 | |||
AG + AA | 46 | 54.12 | 63 | 42.57 | 1.585 | 0.929 | 2.704 | 0.090 | ||
GG + AG | 74 | 87.06 | 138 | 93.24 | 0.491 | 0.203 | 1.187 | 0.113 | ||
G | 113 | 66.47 | 223 | 75.34 | 1 | |||||
A | 57 | 33.53 | 73 | 24.66 | 1.541 | 1.020 | 2.327 | 0.040 | ||
rs4239242 | ||||||||||
TT | 30 | 35.29 | 60 | 40.54 | 1 | 0.309 | ||||
CT | 35 | 41.18 | 65 | 43.92 | 1.075 | 0.592 | 1.953 | |||
CC | 20 | 23.53 | 23 | 15.54 | 1.730 | 0.830 | 3.609 | |||
CT + CC | 55 | 64.71 | 88 | 59.46 | 1.244 | 0.718 | 2.155 | 0.429 | ||
TT + CT | 65 | 76.47 | 125 | 84.46 | 0.598 | 0.308 | 1.162 | 0.131 | ||
T | 95 | 55.88 | 185 | 62.50 | 1 | |||||
C | 75 | 44.12 | 111 | 37.50 | 1.315 | 0.897 | 1.928 | 0.161 | ||
rs4794976 | ||||||||||
TT | 36 | 42.35 | 83 | 56.08 | 1 | 0.060 | ||||
GT | 31 | 36.47 | 48 | 32.43 | 1.486 | 0.821 | 2.690 | |||
GG | 18 | 21.18 | 17 | 11.49 | 2.418 | 1.130 | 5.174 | |||
GT + GG | 49 | 57.65 | 65 | 43.92 | 1.729 | 1.011 | 2.955 | 0.044 | ||
TT + GT | 67 | 78.82 | 131 | 88.51 | 0.486 | 0.237 | 0.994 | 0.047 | ||
T | 103 | 60.59 | 214 | 72.30 | 1 | |||||
G | 67 | 39.41 | 82 | 27.70 | 1.696 | 1.139 | 2.525 | 0.009 |
Haplotype * | ccRCC (%) | Control (Freq) | Odds Ratio [95% CI] | p-Value |
---|---|---|---|---|
A A | 9.00 (1.9) | 35.95 (4.4) | 0.421 [0.201~0.882] | 0.018 |
A C | 372.00 (78.5) | 611.05 (74.7) | 1.235 [0.943~1.617] | 0.125 |
C C | 93.00 (19.6) | 170.95 (20.9) | 0.924 [0.697~1.225] | 0.583 |
Global χ2 = 6.18, df = 2, p = 0.046 |
Haplotype * | ccRCC (%) | Control (%) | Odds Ratio [95% CI] | p-Value |
---|---|---|---|---|
A A C G | 120.88 (25.8) | 168.59 (20.7) | 1.335 [1.021~1.746] | 0.034 |
A A C T | 0.00 (0) | 11.03 (1.4) | - | 0.011 |
G A C G | 11.02 (2.4) | 9.88 (1.2) | 1.964 [0.826~4.672] | 0.120 |
G A T T | 1.05 (0.2) | 13.43 (1.6) | 0.134 [0.018~0.980] | 0.020 |
G G C G | 11.86 (2.5) | 20.90 (2.6) | 0.987 [0.480~2.032] | 0.972 |
G G C T | 40.24 (8.6) | 67.47 (8.3) | 1.041 [0.692~1.567] | 0.846 |
G G T G | 14.24 (3.0) | 28.41 (3.5) | 0.868 [0.455~1.658] | 0.668 |
G G T T | 262.59 (56.1) | 483.95 (59.3) | 0.870 [0.690~1.098] | 0.241 |
Global χ2 = 18.30, df = 7, p = 0.011 |
Univariate | Multivariate | ||||||||
---|---|---|---|---|---|---|---|---|---|
Variable | HR | 95% CI | p-Value | HR | 95% CI | p-Value | |||
Age at diagnosis | 1.03 | 1.01 | 1.05 | 0.002 | 1.03 | 1.01 | 1.06 | 0.007 | |
Stage of disease (ref. I) | II | 0.29 | 0.14 | 0.63 | 0.001 | - | - | - | - |
III | 3.68 | 2.17 | 6.25 | 0.502 | - | - | - | - | |
IV | 34.31 | 14.38 | 81.88 | <0.001 | - | - | - | - | |
Metastasis (ref. no) | Present | 4.80 | 3.23 | 7.13 | <0.001 | 3.64 | 2.22 | 5.94 | <0.001 |
Necrosis (ref. no) | Present | 2.61 | 1.74 | 3.89 | <0.001 | 1.63 | 1.01 | 2.63 | 0.048 |
Tumor size (ref. ≤ 70) | >70 mm | 2.48 | 1.69 | 3.64 | <0.001 | 1.73 | 1.06 | 2.82 | 0.027 |
Sex (ref. female) | Male | 1.51 | 1.02 | 2.21 | 0.038 | 1.79 | 1.08 | 2.97 | 0.023 |
rs1036199 (ref. AA) | AC + CC | 1.54 | 1.08 | 2.19 | 0.017 | 1.96 | 1.25 | 3.07 | 0.003 |
rs10057302 (ref. CC) | AC + AA | 1.15 | 0.47 | 2.83 | 0.753 | - | - | - | - |
rs3751093 (ref. GG) | AG + AA | 0.98 | 0.69 | 1.39 | 0.908 | - | - | - | - |
rs361497 (ref. GG) | AG + AA | 0.89 | 0.62 | 1.27 | 0.511 | - | - | - | - |
rs4239242 (ref. TT) | CT + CC | 0.91 | 0.64 | 1.30 | 0.608 | - | - | - | - |
rs4794976 (ref. TT) | GT + GG | 1.02 | 0.72 | 1.45 | 0.918 | - | - | - | - |
Variable | All N = 237 | Male N = 151 | Female N = 86 | |||
---|---|---|---|---|---|---|
Age at Diagnosis | ||||||
Median | 62 | 61 | 63 | |||
Mean | 62.61 | 62.01 | 63.67 | |||
Q1–Q3 | 56–70 | 56–68 | 58–71 | |||
Min., max. | 21, 85 | 21, 85 | 24, 85 | |||
BMI | ||||||
Median | 27.7 | 27.7 | 27.75 | |||
Mean | 28.29 | 28.26 | 28.33 | |||
Q1–Q3 | 24.6–31.5 | 25.1–30.7 | 23.85–31.2 | |||
Min., max. | 19.1, 43.8 | 19.7, 43.8 | 19.1, 43.8 | |||
Stage of Disease | N | % | N | % | N | % |
I | 108 | (45.57) | 63 | (41.72) | 45 | (52.33) |
II | 26 | (10.97) | 20 | (13.25) | 6 | (6.98) |
III | 26 | (10.97) | 16 | (10.60) | 10 | (11.63) |
IV | 76 | (32.07) | 51 | (33.77) | 25 | (29.07) |
Unknown | 1 | (0.42) | 1 | (0.66) | 0 | (0) |
Metastasis | ||||||
No | 165 | (69.62) | 101 | (66.89) | 64 | (74.42) |
Present | 53 | (22.36) | 35 | (23.18) | 18 | (20.93) |
Unknown | 19 | (8.02) | 15 | (9.93) | 4 | (4.65) |
Necrosis | ||||||
No | 118 | (59.00) | 71 | (55.47) | 47 | (65.28) |
Present | 82 | (41.00) | 57 | (44.53) | 25 | (34.72) |
Unknown | 0 | (0) | 0 | (0) | 0 | (0) |
Tumor Size | ||||||
<70 mm | 143 | 60.34 | 87 | (57.61) | 56 | (65.12) |
>70 mm | 65 | 27.42 | 48 | (31.79) | 17 | (19.77) |
Unknown | 29 | 12.24 | 16 | (10.60) | 13 | (15.11) |
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Andrzejczak, A.; Tupikowski, K.; Tomkiewicz, A.; Małkiewicz, B.; Ptaszkowski, K.; Domin, A.; Szydełko, T.; Karabon, L. The Variations’ in Genes Encoding TIM-3 and Its Ligand, Galectin-9, Influence on ccRCC Risk and Prognosis. Int. J. Mol. Sci. 2023, 24, 2042. https://doi.org/10.3390/ijms24032042
Andrzejczak A, Tupikowski K, Tomkiewicz A, Małkiewicz B, Ptaszkowski K, Domin A, Szydełko T, Karabon L. The Variations’ in Genes Encoding TIM-3 and Its Ligand, Galectin-9, Influence on ccRCC Risk and Prognosis. International Journal of Molecular Sciences. 2023; 24(3):2042. https://doi.org/10.3390/ijms24032042
Chicago/Turabian StyleAndrzejczak, Anna, Krzysztof Tupikowski, Anna Tomkiewicz, Bartosz Małkiewicz, Kuba Ptaszkowski, Aleksandra Domin, Tomasz Szydełko, and Lidia Karabon. 2023. "The Variations’ in Genes Encoding TIM-3 and Its Ligand, Galectin-9, Influence on ccRCC Risk and Prognosis" International Journal of Molecular Sciences 24, no. 3: 2042. https://doi.org/10.3390/ijms24032042