GPX3 rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. DNA Isolation
2.3. Genotyping
2.4. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variable | Patients, n = 209 | Controls, n = 140 | p |
---|---|---|---|
Sex | |||
Male, n (%) | 117 (56) | 71 (51) | |
Female, n (%) | 92 (44) | 69 (49) | 0.146 |
Age (years) * | 71.67 ± 6.54 | 70.29 ± 6.94 | 0.153 |
Smoking, n (%) ** | |||
Yes | 69 (33) | 37 (27) | |
No | 137 (67) | 98 (73) | 0.236 |
Upper tract urothelial carcinoma, | |||
n (%) ** | |||
Yes | 32 (15) | // | |
No | 177 (85) | // | - |
Genotype | Patients, n (%) | Controls, n (%) | OR a 1 (95% CI) b | p | OR 2 (95% CI) | p | OR 3 (95% CI) | p | OR 4 (95% CI) | p |
---|---|---|---|---|---|---|---|---|---|---|
KEAP1 rs1048290 | ||||||||||
*C/C c | 35 (16) | 22 (16) | 1.0 c | - | 1.0 c | - | 1.0 c | - | 1.0 c | - |
*C/G | 87 (42) | 61 (43) | 0.89 (0.48–1.67) | 0.732 | 0.86 (0.45–1.63) | 0.861 | 0.91 (0.48 1.72) | 0.791 | 0.90 (0.46–1.74) | 0.759 |
*G/G | 87 (42) | 57 (41) | 0.95 (0.51–1.8) | 0.897 | 0.90 (0.54–2.08) | 0.763 | 0.97 (0.51–1.84) | 0.940 | 0.96 (0.49–1.87) | 0.920 |
*C/G*G/G | 174 (84) | 118 (84) | 0.92 (0.51–1.65) | 0.798 | 0.88 (0.49–1.6) | 0.688 | 0.94 (0.52–1.70) | 0.853 | 0.93 (0.51–1.70) | 0.834 |
Nrf2 rs6721961 | ||||||||||
*C/C c | 158 (76) | 103 (74) | 1.0 c | - | 1.0 c | - | 1.0 c | - | 1.0 c | - |
*C/A | 45 (21) | 34 (24) | 0.86 (0.52–1.44) | 0.571 | 0.88 (0.53–1.48) | 0.648 | 0.86 (0.51–1.45) | 0.587 | 0.89 (0.52–1.51) | 0.671 |
*A/A | 6 (3) | 3 (2) | 1.30 (0.32–0.33) | 0.712 | 0.90 (0.19–4.17) | 0.901 | 1.15 (0.27–4.75) | 0.847 | 0.67 (0.14–3.21) | 0.625 |
*C/A*A/A | 51(24) | 37(26) | 0.88 (0.55–1.46) | 0.669 | 0.91 (0.55–1.50) | 0.723 | 0.89 (0.54–1.46) | 0.648 | 0.83 (0.48–1.42) | 0.608 |
GSTP1 AB rs1695 | ||||||||||
*A/A c | 96 (45) | 64 (46) | 1.0 c | - | 1.0 c | - | 1.0 c | 1.0 c | - | |
*A/G | 95 (46) | 67 (48) | 0.94 (0.60–1.47) | 0.804 | 0.92 (0.58–1.46) | 0.737 | 0.91 (0.58–1.44) | 0.710 | 0.98 (0.61–1.56) | 0.930 |
*G/G | 18 (9) | 9 (6) | 1.33 (0.56–3.15) | 0.512 | 1.04 (0.42–2.57) | 0.931 | 1.34 (0.56–3.21) | 0.501 | 0.93 (0.36–2.24) | 0.894 |
*A/G*G/G | 113 (55) | 76 (54) | 0.99 (0.64–1.52) | 0.968 | 0.94 (0.60–1.47) | 0.814 | 0.96 (0.62–1.49) | 0.887 | 0.97 (0.62–1.53) | 0.913 |
GSTP1 CD rs1138272 | ||||||||||
*C/C c | 187 (89) | 129(92) | 1.0 c | - | 1.0 c | - | 1.0 c | - | 1.0 c | - |
*C/T | 17 (8) | 11(8) | 1.06 (0.48–2.35) | 0.874 | 1.07 (0.47–2.41) | 0.864 | 1.01 (0.45–2.26) | 0.967 | 0.96 (0.61–1.56) | 0.926 |
*T/T | 5 (3) | 0(0) | NA d | NA | NA | NA | NA | NA | NA | NA |
*C/T*T/T | 22(11) | 11 (8) | 1.38 (0.64–2.94) | 0.405 | 1.40 (0.64–3.04) | 0.396 | 1.35 (0.63–2.90) | 0.438 | 1.31 (0.59–2.90) | 0.505 |
GPX3 rs8177412 | ||||||||||
*T/T c | 159(76) | 112 (80) | 1.0 c | - | 1.0 c | - | 1.0 c | - | 1.0 c | - |
*T/C | 49 (23) | 26 (19) | 1.32 (0.77–2.26) | 0.298 | 1.30 (0.75–2.25) | 0.124 | 1.33 (0.77–2.78) | 0.294 | 1.30 (0.74–2.25) | 0.351 |
*C/C | 1 (1) | 2 (1) | 0.35 (0.03–3.93) | 0.397 | 0.37 (0.32–4.34) | 0.429 | 0.40 (0.03–4.50) | 0.459 | 0.45 (0.03–5.23) | 0.526 |
*T/C*C/C | 50 (24) | 28 (20) | 1.25 (0.74–2.12) | 0.389 | 1.24 (0.73–2.11) | 0.415 | 1.26 (0.75–2.14) | 0.374 | 1.26 (0.74–2.15) | 0.392 |
MDR1 rs1045642 | ||||||||||
*C/C c | 39 (20) | 36 (26) | 1.0 c | - | 1.0 c | - | 1.0 c | - | 1.0 c | - |
*C/T | 100 (49) | 69 (49) | 1.33 (0.77–2.31) | 0.297 | 1.31 (0.75–2.29) | 0.341 | 1.37 (0.78–2.38) | 0.263 | 1.35 (0.77–2.39) | 0.290 |
*T/T | 43 (31) | 35 (25) | 1.66 (0.90–3.06) | 0.105 | 1.55 (0.83–2.90) | 0.164 | 1.82 (0.97–3.40) | 0.059 | 1.70 (0.99–3.22) | 0.099 |
*C/T*T/T | 143 (80) | 104 (74) | 1.44 (0.86–2.42) | 0.160 | 1.45 (0.86–2.44) | 0.159 | 1.51 (0.90–2.56) | 0.117 | 1.47 (0.86–2.50) | 0.149 |
Genotype | BEN, n (%) | Controls, n (%) | OR 1 a (95% CI) b | p | OR 2 (95% CI) | p | |
---|---|---|---|---|---|---|---|
GPX3 rs8177412+ MDR1 rs1045642 | |||||||
GPX3*TT/MDR1*CC | 33 (16) | 31 (22) | 1.0 c | - | 1.0 c | - | |
GPX3*TT/MDR1*CT*TT | 120( 60) | 81 (58) | 1.39 (0.79–2.45) | 0.252 | 1.46 (0.82–2.60) | 0.193 | |
GPX3*CC*TC/MDR1*CC | 6 (3) | 5 (4) | 1.12 (0.31–4.07) | 0.855 | 1.16 (0.31–4.22) | 0.820 | |
GPX3*CC*TC/MDR1*CT*TT | 43 (21) | 23 (16) | 1.75 (0.86–3.55) | 0.117 | 1.86 (0.91–3.80) | 0.087 | |
Nrf2 rs6721961+ KEAP1 rs1048290 | |||||||
Nrf2*CC/KEAP1*CC | 25 (12) | 18 (13) | 1.0 c | - | 1.0 c | - | |
Nrf2*CC/KEAP1*CG*GG | 10 (5) | 4 (3) | 1.80 (0.48–6.62) | 0.379 | 1.91 (0.51–7.14) | 0.335 | |
Nrf2*CA*AA/KEAP1*CC | 133 (63) | 85 (61) | 1.12 (0.58–2.18) | 0.725 | 1.17 (0.60–2.30) | 0.634 | |
Nrf2*CA*AA/KEAP1*CG*GG | 41(20) | 33 (23) | 0.89 (0.41–1.91) | 0.774 | 0.91 (0.42–1.96) | 0.818 | |
Nrf2 rs6721961+ MDR1 rs1045642 | |||||||
Nrf2*CC/MDR1*CC | 31 (15) | 28 (20) | 1.0 c | - | 1.0 c | - | |
Nrf2*CC/MDR1*CT*TT | 121 (60) | 75 (53) | 1.45 (0.81–2.62) | 0.208 | 1.52 (0.83–2.75) | 0.167 | |
Nrf2*CA*AA/MDR1*CC | 8 (4) | 8 (6) | 0.90 (0.29–2.72) | 0.857 | 0.87 (0.28–2.68) | 0.811 | |
Nrf2*CA*AA/MDR1*CT*TT | 42 (21) | 29 (21) | 1.30 (0.65–2.62) | 0.450 | 1.35 (0.67–2.74) | 0.396 | |
Nrf2 rs6721961+ GSTP1AB rs1695 | |||||||
Nrf2*CC/GSTP1AB*AA | 70 (34) | 43 (31) | 1.0 c | - | 1.0 c | - | |
Nrf2*CC/GSTP1AB*AG*GG | 88 (42) | 60 (43) | 0.90 (0.54–1.48) | 0.684 | 0.87 (0.52–1.44) | 0.599 | |
Nrf2*CA*AA/GSTP1AB*AA | 26 (12) | 21 (15) | 0.76 (0.38–1.51) | 0.436 | 0.74 (0.37–1.48) | 0.399 | |
Nrf2*CA*AA/GSTP1AB*AG*GG | 25 (12) | 16 (11) | 0.96 (0.46–1.99) | 0.913 | 0.93 (0.44–1.95) | 0.856 | |
Nrf2 rs6721961+ GSTP1CD rs1138272 | |||||||
Nrf2*CC/GSTPD*CC | 141 (68) | 95 (68) | 1.0 c | - | 1.0 c | - | |
Nrf2*CC/GSTP1CD*CT*TT | 17 (8) | 8 (6) | 1.43 (0.59–3.45) | 0.424 | 1.36 (0.56–3.31) | 0.494 | |
Nrf2*CA*AA/GSTP1CD*CC | 46 (22) | 34 (24) | 0.91 (0.54–1.52) | 0.724 | 0.89 (0.53–1.50) | 0.675 | |
Nrf2*CA*AA/GSTP1CD*CT*TT | 5 (2) | 3 (2) | 1.12 (0.26–4.81) | 0.876 | 1.18 (0.27–5.14) | 0.825 |
Genotype | BEN, n (%) | Controls, n (%) | OR 1 a (95% CI) b | p | OR 2 (95% CI) | p |
---|---|---|---|---|---|---|
GPX3 rs8177412+ MDR1 rs1045642 | ||||||
GPX3*TT/MDR1*CC | 13 (14) | 17 (24) | 1.0 c | - | 1.0 c | - |
GPX3*TT/MDR1*CT*TT | 51 (57) | 43 (60) | 1.55 (0.67–3.55) | 0.299 | 1.85 (0.78–4.40) | 0.163 |
GPX3*CC*TC/MDR1*CC | 3 (3) | 2 (3) | 1.96 (0.28–13.50) | 0.494 | 2.11 (0.30–14.74) | 0.451 |
GPX3*CC*TC/MDR1*CT*TT | 23 (26) | 9 (13) | 3.34 (1.16–9.60) | 0.025 * | 3.79 (1.27–11.24) | 0.016 * |
Nrf2 rs6721961+ KEAP1 rs1048290 | ||||||
Nrf2*CC/KEAP1*CC | 6 (7) | 9 (13) | 1.0 c | - | 10 c | - |
Nrf2*CC/KEAP1*CG*GG | 61 (66) | 48 (68) | 1.80 (0.48–6.62) | 0.379 | 1.87 (0.61–5.71) | 0.269 |
Nrf2*CA*AA/KEAP1*CC | 5 (5) | 2 (2) | 1.12 (0.58–2.18) | 0.725 | 3.65 (0.51–25.73) | 0.194 |
Nrf2*CA*AA/KEAP1*CG*GG | 20(22) | 12 (17) | 0.89 (0.41–1.91) | 0.774 | 2.35 (0.65–8.40) | 0.187 |
Nrf2 rs6721961+ MDR1 rs1045642 | ||||||
Nrf2*CC/MDR1*CC | 13 (15) | 18 (25) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/MDR1*CT*TT | 52 (57) | 39 (55) | 1.84 (0.80–4.21) | 0.145 | 2.19 (0.92–5.18) | 0.074 |
Nrf2*CA*AA/MDR1*CC | 3 (3) | 1 (1) | 4.15 (0.38–44.50) | 0.240 | 4.07 (0.36–44.97) | 0.252 |
Nrf2*CA*AA/MDR1*CT*TT | 22 (25) | 13 (19) | 2.34 (0.87–6.30) | 0.092 | 2.60 (0.94–7.18) | 0.065 |
Nrf2 rs6721961+ GSTP1AB rs1695 | ||||||
Nrf2*CC/GSTP1AB*AA | 29 (32) | 27 (38) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/GSTP1AB*AG*GG | 38 (41) | 30 (42) | 1.17 (0.58–2.39) | 0.649 | 1.05 (0.50–2.18) | 0.886 |
Nrf2*CA*AA/GSTP1AB*AA | 12 (13) | 8 (11) | 1.39 (0.49–3.93) | 0.528 | 1.30 (0.45–3.73) | 0.620 |
Nrf2*CA*AA/GSTP1AB*AG*GG | 13 (14) | 6 (9) | 2.07 (0.67–6.06) | 0.211 | 1.76 (0.57–5.38) | 0.319 |
Nrf2 rs6721961+ GSTP1CD rs1138272 | ||||||
Nrf2*CC/GSTP1CD*CC | 63 (69) | 53 (75) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/GSTP1CD*CT*TT | 4 (4) | 4 (6) | 1.05 (0.50–2.18) | 0.886 | 0.70 (0.16–3.09) | 0.648 |
Nrf2*CA*AA/GSTP1CD*CC | 22 (24) | 13 (18) | 1.30 (0.45–3.73) | 0.620 | 1.33 (0.60–2.92) | 0.477 |
Nrf2*CA*AA/GSTP1CD*CT*TT | 3 (3) | 1 (1) | 1.76 (0.57–5.38) | 0.319 | 2.75 (0.27–27.82) | 0.389 |
Genotype | BEN, n (%) | Controls, n (%) | OR 1 a (95% CI) b | p | OR 2 (95% CI) | p |
---|---|---|---|---|---|---|
GPX3 rs8177412+ MDR1 rs1045642 | ||||||
GPX3*TT/MDR1*CC | 20 (18) | 14 (20) | 1.0 c | - | 1.0 c | - |
GPX3*TT/MDR1*CT*TT | 69(61) | 38 (55) | 1.27 (0.57–2.79) | 0.552 | 1.27 (0.57–2.81) | 0.547 |
GPX3*CC*TC/MDR1*CC | 3 (3) | 3 (4) | 0.70 (0.12–3.98) | 0.688 | 0.70 (0.12–4.05) | 0.699 |
GPX3*CC*TC/MDR1*CT*TT | 20 (18) | 14 (21) | 1.00 (0.38–2.67) | 1.000 | 1.02 (0.38–2.691) | 0.996 |
Nrf2 rs6721961+ KEAP1 rs1048290 | ||||||
Nrf2*CC/KEAP1*CC | 19 (16) | 9 (13) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/KEAP1*CG*GG | 72 (62) | 37 (54) | 0.85 (0.38–2.23) | 0.857 | 0.92 (0.38–2.24) | 0.861 |
Nrf2*CA*AA/KEAP1*CC | 5 (4) | 2 (3) | 1.18 (0.19–7.32) | 0.856 | 1.20 (0.19–7.45) | 0.842 |
Nrf2*CA*AA/KEAP1*CG*GG | 21(18) | 21 (30) | 0.47 (0.17–1.28) | 0.142 | 0.47 (0.17–1.30) | 0.148 |
Nrf2 rs6721961+ MDR1 rs1045642 | ||||||
Nrf2*CC/MDR1*CC | 18 (16) | 10 (15) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/MDR1*CT*TT | 69 (62) | 36 (52) | 1.06 (0.44–2.54) | 0.888 | 1.07 (0.44–2.57) | 0.872 |
Nrf2*CA*AA/MDR1*CC | 5 (4) | 7 (10) | 0.39 (0.09–1.58) | 0.190 | 0.40 (0.10–1.61) | 0.199 |
Nrf2*CA*AA/MDR1*CT*TT | 20 (18) | 16 (23) | 0.69 (0.25–1.91) | 0.481 | 0.70 (0.25–1.95) | 0.501 |
Nrf2 rs6721961+ GSTP1AB rs1695 | ||||||
Nrf2*CC/GSTP1AB*AA | 41 (35) | 16 (23) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/GSTP1AB*AG*GG | 50 (43) | 30 (43) | 0.65 (0.32–1.35) | 0.251 | 0.65 (0.31–1.37) | 0.264 |
Nrf2*CA*AA/GSTP1AB*AA | 14 (12) | 13 (19) | 0.42 (0.16–1.08) | 0.074 | 0.42 (0.16–1.10) | 0.079 |
Nrf2*CA*AA/GSTP1AB*AG*GG | 12 (10) | 10 (15) | 0.46 (0.16–1.29) | 0.144 | 0.47 (0.17–1.32) | 0.155 |
Nrf2 rs6721961+ GSTP1CD rs1138272 | ||||||
Nrf2*CC/GSTP1CD*CC | 78 (67) | 42 (61) | 1.0 c | - | 1.0 c | - |
Nrf2*CC/GSTP1CD*CT*TT | 13 (11) | 4 (6) | 1.75 (0.53–5.75) | 0.353 | 1.78 (0.54–5.82) | 0.339 |
Nrf2*CA*AA/GSTP1CD*CC | 24 (21) | 21 (30) | 0.61 (0.30–1.23) | 0.171 | 0.62 (0.31–1.25) | 0.184 |
Nrf2*CA*AA/GSTP1CD*CT*TT | 2 (1) | 2 (3) | 0.53 (0.07–3.96) | 0.543 | 0.54 (0.07–4.03) | 0.553 |
L1 | L2 | D′ | LOD | r2 | 95% CI |
---|---|---|---|---|---|
GSTP1ABrs1695 | GSTP1CDrs1138272 | 0.647 | 4.63 | 0.051 | 0.41–0.80 |
Genotype | Haplotype Frequencies | |||||
---|---|---|---|---|---|---|
rs1695 | rs1138272 | BEN, % | Controls, % | OR (95% CI) a | p | |
GSTP1A d | *A | *C | 68 | 70 | 1.00 c | |
GSTP1B e | *G | *C | 26 | 27 | 1.01 (0.70–1.45) | 0.970 |
GSTP1C f | *G | *T | 5 | 3 | 1.64 (0.75–3.58) | 0.210 |
GSTP1D g | *A | *T | 1 | 0 | NA b | NA |
Genotype | BEN, n (%) | Controls, n (%) | OR 1 a (95% CI) b | p |
---|---|---|---|---|
1 c | 20 (10) | 16 (11) | 1.00 c | - |
2 | 65 (32) | 45 (32) | 1.32 (0.57–2.68) | 0.591 |
3 | 71 (35) | 48 (34) | 1.04 (0.45–2.43) | 0.916 |
4 | 33 (16) | 26 (18) | 2.32 (0.62–8.71) | 0.210 |
5 | 12 (6) | 4 (3) | 3.04 (0.74–12.3) | 0.120 |
Genotype | BEN with Tumors, n = 32 n (%) | BEN without Tumors, n = 177 n (%) | ORa 1 (95% CI) b | p | OR 2 (95% CI) | p |
---|---|---|---|---|---|---|
KEAP1 rs1048290 | ||||||
*CC | 4 (12) | 31 (18) | 1.0 c | - | 1.0 c | - |
*CG*GG | 28 (88) | 146 (82) | 1.48 (0.48–4.52) | 0.487 | 0.84 (0.34–2.02) | 0.718 |
Nrf2 rs6721961 | ||||||
*CC | 25 (78) | 133 (75) | 1.0 c | - | 1.0 c | - |
*CA*AA | 7 (22) | 44 (25) | 0.84 (0.34–2.09) | 0.718 | 0.83 (0.33–2.07) | 0.693 |
GSTP1AB rs1695 | ||||||
*AA | 12 (38) | 84 (47) | 1.0 c | - | 1.0 c | - |
*AG*GG | 20 (62) | 93 (53) | 1.30 (0.69–3.26) | 0.500 | 1.41 (0.64–3.10) | 0.382 |
GSTP1CD rs1138272 | ||||||
*CC | 27 (84) | 160 (90) | 1.0 c | - | 1.0 c | - |
*CT*TT | 5 (16) | 17 (10) | 1.71 (0.59–5.11) | 0.312 | 1.84 (0.61–5.53) | 0.275 |
GPX3 rs8177412 | ||||||
*TT | 12 (38) | 147 (83) | 1.0 c | - | 1.0 c | - |
*CC*TC | 20 (62) | 30 (17) | 8.16 (3.60–18.40) | 0.001 * | 8.48 (3.60–19.30) | 0.001 * |
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Radic Savic, Z.; Coric, V.; Vidovic, S.; Vidovic, V.; Becarevic, J.; Milovac, I.; Reljic, Z.; Mirjanic-Azaric, B.; Skrbic, R.; Gajanin, R.; et al. GPX3 rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy. Medicina 2023, 59, 1421. https://doi.org/10.3390/medicina59081421
Radic Savic Z, Coric V, Vidovic S, Vidovic V, Becarevic J, Milovac I, Reljic Z, Mirjanic-Azaric B, Skrbic R, Gajanin R, et al. GPX3 rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy. Medicina. 2023; 59(8):1421. https://doi.org/10.3390/medicina59081421
Chicago/Turabian StyleRadic Savic, Zana, Vesna Coric, Stojko Vidovic, Vanja Vidovic, Jelena Becarevic, Irina Milovac, Zorica Reljic, Bosa Mirjanic-Azaric, Ranko Skrbic, Radoslav Gajanin, and et al. 2023. "GPX3 rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy" Medicina 59, no. 8: 1421. https://doi.org/10.3390/medicina59081421