The Impact of ARMS2 (rs10490924), VEGFA (rs3024997), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), and IL1B1 (rs1143623) Polymorphisms and Serum Levels on Age-Related Macular Degeneration Development and Therapeutic Responses
Abstract
:1. Introduction
2. Results
2.1. Hardy–Weinberg Equilibrium Analysis
2.2. VEGFA rs3024997, IL1B rs1143623, TNFRSF1B rs1061622, TNFRSF1A rs4149576, and ARMS2 rs10490924 Associations with Early and Exudative AMD
Analysis of VEGFA rs3024997, IL1B rs1143623, TNFRSF1B rs1061622, TNFRSF1A rs4149576, and ARMS2 rs10490924 in Early and Exudative AMD in Female and Male Subgroups
2.3. Serum IL1B, TNFRSF1B, TNFRSF1A, and ARMS2 Associations with Early and Exudative AMD
2.4. Serum IL1B, TNFRS1B, TNFRS1A, and ARMS2 Levels and IL1B, TNFRS1B, TNFRS1A, and ARMS2 SNP Associations with AMD
2.5. Response to Exudative AMD Treatment with Anti-VEGF Injections
2.6. Single-Nucleotide Polymorphism Associations with Exudative AMD Treatment Response
2.7. Serum IL1B, TNFRSF1B, TNFRSF1A, and ARMS2 Associations with the Treatment Response to Anti-VEGF Treatment
3. Discussion
3.1. Genetic Variants and AMD
3.2. Serum Biomarkers and AMD
3.3. Response to Anti-VEGF Treatment
4. Materials and Methods
4.1. Ethics
4.2. Study Design and Structure
4.3. SNP Selection
4.4. Study Group Formation
4.5. Exudative AMD Response to Anti-VEGF Injection Treatment
4.6. DNA Extraction from Peripheral Venous Blood and Genotyping
4.7. Serum Protein Concentration Measurement
4.8. 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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Characteristic | Early AMD n = 253 | Exudative AMD n = 245 | Control n = 337 | p-Value |
---|---|---|---|---|
Gender 2 Males, n (%) Females, n (%) | 80 (31.6) 173 (68.4) | 90 (36.7) 155 (63.3) | 115 (34.1) 222 (65.9) | 0.522 * 0.515 ** |
Age years; median (IQR) 1 | 73 (12) | 77 (10) | 72 (11) | 0.117 * <0.001 ** |
Gene/Marker | Genotype/ Allele | Group | p-Value * | p-Value ** | ||
---|---|---|---|---|---|---|
Early AMD (n = 253) n (%) | Exudative AMD (n = 245) n (%) | Control (n = 337) n (%) | ||||
VEGFA rs3024997 | GG GA AA G A | 150 (59.3) 86 (34) 17 (6.7) 386 (76.3) 120 (23.7) | 155 (63.3) 89 (36.3) 1 (0.4) 399 (81.4) 91 (18.6) | 187 (55.5) 129 (38.3) 21 (6.2) 503 (74.6) 171 (25.4) | 0.563 0.513 | <0.001 0.006 |
IL1B rs1143623 | CC CG GG C G | 129 (51) 103 (40.7) 21 (8.3) 361 (71.3) 145 (28.7) | 134 (54.7) 92 (37.6) 19 (7.8) 360 (73.5) 130 (26.5) | 173 (51.3) 143 (42.4) 21 (6.2) 489 (72.6) 185 (27.4) | 0.614 0.647 | 0.445 0.727 |
TNFRSF1B rs1061622 | GG GT TT G T | 161 (63.6) 79 (31.2) 13 (5.1) 401 (79.2) 105 (20.8) | 157 (64.1) 74 (30.2) 14 (5.7) 388 (79.2) 102 (20.8) | 220 (65.3) 107 (31.8) 10 (3) 547 (81.2) 127 (18.8) | 0.402 0.414 | 0.225 0.403 |
TNFRSF1A rs4149576 | TT TC CC T C | 61 (24.1) 123 (48.6) 69 (27.3) 245 (48.4) 261 (51.6) | 60 (24.5) 124 (50.6) 61 (24.9) 244 (49.8) 246 (50.2) | 89 (26.4) 168 (49.9) 80 (23.7) 346 (51.3) 328 (48.7) | 0.589 0.321 | 0.861 0.604 |
ARMS2 rs10490924 | GG GT TT G T | 116 (45.8) 108 (42.7) 29 (11.5) 340 (67.2) 166 (32.8) | 78 (31.8) 106 (43.3) 61 (24.9) 262 (53.5) 228 (46.5) | 183 (54.3) 129 (38.3) 25 (7.4) 495 (73.4) 179 (26.6) | 0.070 0.019 | <0.001 <0.001 |
VEGFA (rs3024997) | ||||
---|---|---|---|---|
Model | Genotype/Allele | OR * (95% CI) | p-Value | AIC |
Codominant | GA vs. GG AA vs. GG | 0.887 (0.617–1.275) 0.047 (0.006–0.366) | 0.518 0.003 | 718.602 |
Dominant | GA + AA vs. GG | 0.755 (0.530–1.076) | 0.120 | 733.422 |
Recessive | AA vs. GG + GA | 0.049 (0.006–0.381) | 0.004 | 717.021 |
Overdominant | GA vs. GG + AA | 0.987 (0.689–1.413) | 0.943 | 735.844 |
Additive | A | 0.657 (0.480–0.899) | 0.009 | 728.805 |
IL1B (rs1143623) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | CG vs. CC GG vs. CC | 0.853 (0.593–1.227) 1.195 (0.599–2.384) | 0.391 0.613 | 736.601 |
Dominant | CG + GG vs. CC | 0.898 (0.634–1.270) | 0.541 | 735.476 |
Recessive | GG vs. CC + CG | 1.279 (0.653–2.508) | 0.473 | 735.336 |
Overdominant | CG vs. CC + GG | 0.835 (0.586–1.190) | 0.319 | 734.856 |
Additive | G | 0.973 (0.737–1.284) | 0.845 | 735.811 |
TNFRSF1B (rs1061622) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | GT vs. GG TT vs. GG | 0.881 (0.603–1.288) 2.049 (0.847–4.957) | 0.514 0.112 | 734.484 |
Dominant | GT + TT vs. GG | 0.974 (0.678–1.399) | 0.888 | 735.829 |
Recessive | TT vs. GG + GT | 2.133 (0.890–5.116) | 0.090 | 732.910 |
Overdominant | GT vs. GG + TT | 0.844 (0.580–1.229) | 0.376 | 735.063 |
Additive | T | 1.078 (0.795–1.462) | 0.627 | 735.614 |
TNFRSF1A (rs4149576) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | TC vs. TT CC vs. TT | 1.140 (0.748–1.737) 1.299 (0.796–2.119) | 0.542 0.296 | 736.752 |
Dominant | TC + CC vs. TT | 1.190 (0.800–1.769) | 0.391 | 735.109 |
Recessive | CC vs. TT + TC | 1.191 (0.796–1.783) | 0.394 | 735.125 |
Overdominant | TC vs. TT + CC | 1.004 (0.711–1.420) | 0.980 | 735.849 |
Additive | C | 1.140 (0.892–1.456) | 0.296 | 734.752 |
ARMS2 (rs10490924) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | GT vs. GG TT vs. GG | 1.768 (1.201–2.603) 5.611 (3.205–9.822) | 0.004 <0.001 | 697.230 |
Dominant | GT + TT vs. GG | 2.377 (1.659–3.404) | <0.001 | 712.955 |
Recessive | TT vs. GG + GT | 4.236 (2.508–7.155) | <0.001 | 703.644 |
Overdominant | GT vs. GG + TT | 1.129 (0.794–1.606) | 0.499 | 735.393 |
Additive | T | 2.200 (1.702–2.846) | <0.001 | 697.423 |
Gene/Marker | Genotype/ Allele | Group | p-Value * | p-Value ** | ||
---|---|---|---|---|---|---|
Early AMD (n = 173) n (%) | Exudative AMD (n = 155) n (%) | Control (n = 222) n (%) | ||||
VEGFA rs3024997 | GG GA AA G A | 103 (59.5) 60 (34.7) 10 (5.8) 266 (76.9) 80 (23.1) | 93 (60) 61 (39.4) 1 (0.6) 247 (79.7) 63 (20.3) | 117 (52.7) 92 (41.4) 13 (5.9) 326 (73.4) 118 (26.6) | 0.373 0.266 | 0.022 0.047 |
IL1B rs1143623 | CC CG GG C G | 93 (53.8) 63 (36.4) 17 (9.8) 249 (72) 97 (28) | 84 (54.2) 56 (36.1) 15 (9.7) 224 (72.3) 86 (27.7) | 110 (49.5) 99 (44.6) 13 (5.9) 319 (71.8) 125 (28.2) | 0.140 0.970 | 0.152 0.901 |
TNFRSF1B rs1061622 | GG GT TT G T | 111 (64.2) 55 (31.8) 7 (4) 277 (80.1) 69 (19.9) | 97 (62.6) 48 (31) 10 (6.5) 242 (78.1) 68 (21.9) | 146 (65.8) 68 (30.6) 8 (3.6) 360 (81.1) 84 (18.9) | 0.937 0.718 | 0.428 0.309 |
TNFRSF1A rs4149576 | TT TC CC T C | 47 (27.2) 78 (45.1) 48 (27.7) 172 (49.7) 174 (50.3) | 33 (21.3) 87 (56.1) 35 (22.6) 153 (49.4) 157 (50.6) | 58 (26.1) 116 (52.3) 48 (21.6) 232 (52.3) 212 (47.7) | 0.279 0.478 | 0.555 0.433 |
ARMS2 rs10490924 | GG GT TT G T | 81 (46.8) 75 (43.4) 17 (9.8) 237 (68.5) 109 (31.5) | 47 (30.3) 72 (46.5) 36 (23.2) 166 (53.5) 144 (46.5) | 120 (54.1) 85 (38.3) 17 (7.7) 325 (73.2) 119 (26.8) | 0.342 0.147 | <0.001 <0.001 |
VEGFA (rs3024997) | ||||
---|---|---|---|---|
Model | Genotype/Allele | OR * (95% CI) | p-Value | AIC |
Codominant | GA vs. GG AA vs. GG | 0.890 (0.561–1.413) 0.074 (0.009–0.624) | 0.622 0.017 | 441.925 |
Dominant | GA + AA vs. GG | 0.777 (0.494–1.221) | 0.273 | 448.552 |
Recessive | AA vs. GG + GA | 0.078 (0.009–0.648) | 0.018 | 440.168 |
Overdominant | GA vs. GG + AA | 0.987 (0.626–1.557) | 0.955 | 449.752 |
Additive | A | 0.680 (0.454–1.018) | 0.061 | 446.194 |
IL1B (rs1143623) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | CG vs. CC GG vs. CC | 0.735 (0.458–1.178) 1.567 (0.660–3.718) | 0.201 0.308 | 448.241 |
Dominant | CG + GG vs. CC | 0.831 (0.531–1.299) | 0.416 | 449.094 |
Recessive | GG vs. CC + CG | 1.793 (0.774–4.152) | 0.173 | 447.886 |
Overdominant | CG vs. CC + GG | 0.693 (0.438–1.097) | 0.117 | 447.285 |
Additive | G | 0.988 (0.694–1.408) | 0.947 | 449.751 |
TNFRSF1B (rs1061622) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | GT vs. GG TT vs. GG | 0.897 (0.548–1.467) 1.919 (0.670–5.494) | 0.664 0.225 | 449.878 |
Dominant | GT + TT vs. GG | 0.996 (0.625–1.588) | 0.986 | 449.755 |
Recessive | TT vs. GG + GT | 1.986 (0.702–5.618) | 0.196 | 448.067 |
Overdominant | GT vs. GG + TT | 0.857 (0.525–1.393) | 0.533 | 449.364 |
Additive | T | 1.096 (0.747–1.608) | 0.638 | 449.536 |
TNFRSF1A (rs4149576) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | TC vs. TT CC vs. TT | 1.472 (0.845–2.564) 1.600 (0.824–3.106) | 0.173 0.165 | 449.329 |
Dominant | TC + CC vs. TT | 1.508 (0.887–2.562) | 0.129 | 447.413 |
Recessive | CC vs. TT + TC | 1.224 (0.716–2.093) | 0.461 | 449.213 |
Overdominant | TC vs. TT + CC | 1.173 (0.749–1.837) | 0.484 | 449.266 |
Additive | C | 1.267 (0.911–1.762) | 0.160 | 447.765 |
ARMS2 (rs10490924) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | GT vs. GG TT vs. GG | 1.979 (1.201–3.261) 5.628 (2.720–11.646) | 0.007 <0.001 | 427.191 |
Dominant | GT + TT vs. GG | 2.550 (1.597–4.071) | <0.001 | 433.851 |
Recessive | TT vs. GG + GT | 3.974 (2.020–7.817) | <0.001 | 432.468 |
Overdominant | GT vs. GG + TT | 1.262 (0.803–1.984) | 0.312 | 448.735 |
Additive | T | 2.265 (1.617–3.172) | <0.001 | 425.703 |
Gene/Marker | Genotype/ Allele | Group | p-Value * | p-Value ** | ||
---|---|---|---|---|---|---|
Early AMD (n = 80) n (%) | Exudative AMD (n = 90) n (%) | Control (n = 115) n (%) | ||||
VEGFA rs3024997 | GG GA AA G A | 47 (58.8) 26 (32.5) 7 (8.8) 120 (75) 40 (25) | 62 (68.9) 28 (31.1) 0 (0) 152 (84.4) 28 (15.6) | 70 (60.9) 37 (32.2) 8 (7) 177 (77) 53 (23) | 0.890 0.655 | 0.034 0.058 |
IL1B rs1143623 | CC CG GG C G | 36 (45) 40 (50) 4 (5) 112 (70) 48 (30) | 50 (55.6) 36 (40) 4 (4.4) 136 (75.6) 44 (24.4) | 63 (54.8) 44 (38.3) 8 (7) 170 (73.9) 60 (26.1) | 0.260 0.395 | 0.745 0.704 |
TNFRSF1B rs1061622 | GG GT TT G T | 50 (62.5) 24 (30) 6 (7.5) 124 (77.5) 36 (22.5) | 60 (66.7) 26 (28.9) 4 (4.4) 146 (81.1) 34 (18.9) | 74 (64.3) 39 (33.9) 2 (1.7) 187 (81.3) 43 (18.7) | 0.131 0.357 | 0.426 0.960 |
TNFRSF1A rs4149576 | TT TC CC T C | 14 (17.5) 45 (56.3) 21 (26.3) 73 (45.6) 87 (54.4) | 27 (30) 37 (41.1) 26 (28.9) 91 (50.6) 89 (49.4) | 31 (27) 52 (45.2) 32 (27.8) 114 (49.6) 116 (50.4) | 0.220 0.443 | 0.826 0.842 |
ARMS2 rs10490924 | GG GT TT G T | 35 (43.8) 33 (41.3) 12 (15) 103 (64.4) 57 (35.6) | 31 (34.4) 34 (37.8) 25 (27.8) 96 (53.3) 84 (46.7) | 63 (54.8) 44 (38.3) 8 (7.0) 170 (73.9) 60 (26.1) | 0.121 0.043 | <0.001 <0.001 |
VEGFA (rs3024997) | ||||
---|---|---|---|---|
Model | Genotype/Allele | OR * (95% CI) | p-Value | AIC |
Codominant | GA vs. GG AA vs. GG | 0.873 (0.479–1.594) - | 0.659 - | 273.752 |
Dominant | GA + AA vs. GG | 0.711 (0.396–1.276) | 0.253 | 280.473 |
Recessive | AA vs. GG + GA | - | - | 271.947 |
Overdominant | GA vs. GG + AA | 0.974 (0.536–1.768) | 0.930 | 281.782 |
Additive | A | 0.616 (0.369–1.028) | 0.064 | 278.221 |
IL1B (rs1143623) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | CG vs. CC GG vs. CC | 1.049 (0.588–1.870) 0.642 (0.182–2.258) | 0.872 0.489 | 283.201 |
Dominant | CG + GG vs. CC | 0.986 (0.565–1.721) | 0.960 | 281.787 |
Recessive | GG vs. CC + CG | 0.629 (0.183–2.163) | 0.462 | 281.227 |
Overdominant | CG vs. CC + GG | 1.093 (0.619–1.928) | 0.759 | 281.696 |
Additive | G | 0.926 (0.585–1.465) | 0.742 | 281.681 |
TNFRSF1B (rs1061622) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | GT vs. GG TT vs. GG | 0.822 (0.450–1.504) 2.526 (0.445–14.345) | 0.525 0.296 | 282.029 |
Dominant | GT + TT vs. GG | 0.904 (0.505–1.619) | 0.735 | 281.675 |
Recessive | TT vs. GG + GT | 2.691 (0.479–15.120) | 0.261 | 280.435 |
Overdominant | GT vs. GG + TT | 0.791 (0.434–1.440) | 0.443 | 281.197 |
Additive | T | 1.017 (0.610–1.695) | 0.948 | 281.786 |
TNFRSF1A (rs4149576) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | TC vs. TT CC vs. TT | 0.811 (0.416–1.583) 0.971 (0.465–2.027) | 0.540 0.938 | 283.321 |
Dominant | TC + CC vs. TT | 0.871 (0.472–1.607) | 0.658 | 281.595 |
Recessive | CC vs. TT + TC | 1.101 (0.593–2.043) | 0.760 | 281.697 |
Overdominant | TC vs. TT + CC | 0.823 (0.469–1.444) | 0.497 | 281.327 |
Additive | C | 0.984 (0.680–1.424) | 0.933 | 281.783 |
ARMS2 (rs10490924) | ||||
Model | Genotype/Allele | OR * (95% CI) | p-value | AIC |
Codominant | GT vs. GG TT vs. GG | 1.537 (0.824–2.867) 6.183 (2.495–15.322) | 0.177 <0.001 | 265.951 |
Dominant | GT + TT vs. GG | 2.251 (1.270–3.989) | 0.005 | 273.879 |
Recessive | TT vs. GG + GT | 5.049 (2.147–11.877) | <0.001 | 265.781 |
Overdominant | GT vs. GG + TT | 0.960 (0.542–1.699) | 0.887 | 281.770 |
Additive | T | 2.205 (1.469–3.310) | <0.001 | 266.193 |
Characteristic | Non-Responders n = 20 | Responders n = 95 | p-Value |
---|---|---|---|
Gender Males, n (%) Females, n (%) | 9 (30) 14 (70) | 29 (30.5) 66 (689.5) | 0.963 * |
Age years; mean (SD) | 75.4 (7.366) | 77.54 (7.784) | 0.263 ** |
Response parameter | |||
VA, median (IQR) Baseline Treated | 0.465 (0.45) 1 0.35 (0.35) 1 | 0.28 (0.26) 2 0.375 (0.35) 2 | 0.018 *** 0.408 *** |
CRT (μm), median (IQR) Baseline Treated | 272.5 (95.25) 3 329 (103) 3 | 320.5 (113) 4 274 (95) 4 | 0.068 *** 0.032 *** |
Genetic Model | Genotype/Allele | Non-Responders n = 20 n (%) | Responders n = 95 n (%) | OR (95% CI) | p-Value | AIC |
---|---|---|---|---|---|---|
Dominant | GT + TT | 3 (15) | 41 (43.2) | 4.302 (1.181; 15.674) | 0.027 | 102.065 |
Additive | T | 3 (7.5) | 48 (25.3) | 3.999 (1.176; 13.602) | 0.026 | 101.291 |
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Cebatoriene, D.; Vilkeviciute, A.; Gedvilaite-Vaicechauskiene, G.; Duseikaite, M.; Bruzaite, A.; Kriauciuniene, L.; Zaliuniene, D.; Liutkeviciene, R. The Impact of ARMS2 (rs10490924), VEGFA (rs3024997), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), and IL1B1 (rs1143623) Polymorphisms and Serum Levels on Age-Related Macular Degeneration Development and Therapeutic Responses. Int. J. Mol. Sci. 2024, 25, 9750. https://doi.org/10.3390/ijms25179750
Cebatoriene D, Vilkeviciute A, Gedvilaite-Vaicechauskiene G, Duseikaite M, Bruzaite A, Kriauciuniene L, Zaliuniene D, Liutkeviciene R. The Impact of ARMS2 (rs10490924), VEGFA (rs3024997), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), and IL1B1 (rs1143623) Polymorphisms and Serum Levels on Age-Related Macular Degeneration Development and Therapeutic Responses. International Journal of Molecular Sciences. 2024; 25(17):9750. https://doi.org/10.3390/ijms25179750
Chicago/Turabian StyleCebatoriene, Dzastina, Alvita Vilkeviciute, Greta Gedvilaite-Vaicechauskiene, Monika Duseikaite, Akvile Bruzaite, Loresa Kriauciuniene, Dalia Zaliuniene, and Rasa Liutkeviciene. 2024. "The Impact of ARMS2 (rs10490924), VEGFA (rs3024997), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), and IL1B1 (rs1143623) Polymorphisms and Serum Levels on Age-Related Macular Degeneration Development and Therapeutic Responses" International Journal of Molecular Sciences 25, no. 17: 9750. https://doi.org/10.3390/ijms25179750