Association Between Genetic Variants in TNF, IL6, and IL1B Genes and Severity of COVID-19: A Cross-Sectional Study of Patients from Southern Brazil
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Data Collection Methodology
- 0 (Asymptomatic): Case explicitly recorded as “asymptomatic” in the system;
- 1 (Mild): No ICU admission, no ventilatory support, and no death;
- 2 (Moderate): Received ventilatory support (non-invasive or invasive), but no ICU admission or death;
- 3 (Severe): ICU admission and/or death.
2.2. DNA Extraction and Genotyping Methods
2.3. Genetic Association Analysis
3. Results
3.1. Symptoms and Comorbidities Associations
3.2. Significant Associations Between IL1B and TNF Genetic Variants and COVID-19 Severity
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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Gene | rsID | Positions * | Chr | Type | Probe | Allele | MAF | DNA Do Brasil ** /ABraOM | HaploReg and ENCODE |
---|---|---|---|---|---|---|---|---|---|
IL1B | rs4848306 | −3737 | 2 | Intergenic | C__11725735_10 | G/A | A (0.36) | 0.36 /0.41 | Involved in inflammatory response; proximal enhancer; maximum activity near the IL1B gene. |
rs1143623 | −1473 | 2 | Intergenic | C___1839941_10 | C/G | C (0.29) | 0.28 /0.25 | Proximal enhancer; involved in the regulation of IL1B expression. | |
rs16944 | −511 | 2 | Intergenic | C___1839943_10 | G/A | G (0.49) | 0.47 /0.41 | Potential inflammatory regulation; located near the IL1B gene, with potential regulatory impact. | |
rs1143627 | −31 | 2 | Intronic | C___1839944_10 | C/T | T (0.47) | 0.49 /0.43 | Potential regulator of inflammatory expression; promoter; maximum activity near IL1B gene. | |
rs1800795 | −174 | 7 | Intronic | C___1839697_20 | G/C | C (0.14) | 0.21 /0.25 | Inflammatory response; promoter; involved in the regulation of IL6 expression. | |
IL6 | rs2069832 | +615 | 7 | Intronic | C__15957646_10 | G/A | A (0.14) | 0.21 /0.25 | Inflammation modulation; promoter; related to increased expression of IL6. |
rs2069840 | +3437 | 7 | Intronic | C__15804104_10 | C/G | G (0.19) | 0.30 /0.29 | Involvement in inflammatory response; intronic; associated with increased expression of IL6. | |
rs2069845 | +3331 | 7 | Intronic | C___1839699_10 | G/A | G (0.25) | 0.34 /0.34 | Involvement in inflammatory response; distal enhancer; related to IL6 expression. | |
TNF | rs1799964 | −1031 | 6 | Intronic | C___7514871_10 | T/C | C (0.22) | 0.16 /0.25 | Potential regulator of inflammatory diseases; proximal enhancer; involved in regulation of TNF expression. |
rs1800630 | −863 | 6 | Intronic | Customized | C/A | A (0.15) | 0.12 /0.18 | Regulation of immune response; proximal enhancer; highly relevant for the regulation of TNF expression. | |
rs1799724 | −857 | 6 | Intronic | C__11918223_10 | C/T | T (0.10) | 0.07 /.011 | Essential for immune response; enhancer; involved in the regulation of TNF. | |
rs1800629 | −308 | 6 | Intronic | C___7514879_10 | G/A | A (0.09) | 0.07 /0.11 | Regulation of inflammatory response; intronic; involved in the modulation of TNF expression. | |
rs361525 | −238 | 6 | Intronic | C___2215707_10 | G/A | A (0.06) | 0.04 /0.06 | Promoter; involved in the regulation of TNF; essential for immune response. |
Non-Hospitalized (n = 235) | Hospitalized (n = 231) | p | Non-ICU (n = 342) | ICU (n = 108) | p | Discharged from the Hospital (n = 337) | Death (n = 125) | p | |
---|---|---|---|---|---|---|---|---|---|
Age | |||||||||
n | 235 | 231 | 342 | 108 | 337 | 125 | |||
Years | 38 [29.0; 53.0] | 65 [51.0; 77.0] | 47 [32.0; 65.0] | 64.5 [50.50; 76.75] | 44 [31.0; 60.0] | 72 [54.0; 80.50] | |||
Total | 52 [36.0; 69.0] | <0.01 * | 51.50 (36.75; 63.50) | <0.01 * | 52.50 [29.0; 61.75] | <0.01 * | |||
Sex | |||||||||
Female | 139 (56.5) | 107 (43.5) | 186 (78.2) | 52 (21.8) | 188 (77.0) | 56 (23.0) | |||
Male | 96 (43.6) | 124 (56.4) | 156 (73.6) | 56 (26.4) | 149 (68.3) | 69 (31.7) | |||
Total | 235 (50.4) | 231 (49.6) | 0.01 ‡ | 342 (76.0) | 108 (24.0) | 0.26 ‡ | 337 (72.9) | 125 (27.1) | 0.04 ‡ |
Comorbidities | |||||||||
Heart conditions | |||||||||
No | 158 (57.0) | 119 (43.0) | 214 (79.3) | 56 (20.7) | 218 (79.3) | 57 (20.7) | |||
Yes | 24 (18.7) | 104 (81.3) | 79 (62.7) | 47 (37.3) | 67 (52.3) | 61 (47.7) | |||
Total | 182 (44.9) | 231 (55.1) | <0.01 ‡ | 293 (74.0) | 103 (26.0) | <0.01 ‡ | 285 (70.7) | 118 (29.3) | <0.01 ‡ |
Chronic lung diseases | |||||||||
No | 175 (47.3) | 195 (52.7) | 270 (74.8) | 91 (25.2) | 266 (72.3) | 102 (27.7) | |||
Yes | 6 (20.7) | 23 (79.3) | 19 (65.5) | 10 (34.5) | 15 (51.7) | 14 (48.3) | |||
Total | 181 (45.4) | 218 (54.6) | 0.01 ‡ | 289 (74.1) | 101 (25.9) | 0.27 ‡ | 281 (70.8) | 116 (29.2) | 0.02 ‡ |
Obesity | |||||||||
No | 173 (49.3) | 178 (50.7) | 266 (77.6) | 77 (22.4) | 255 (73.1) | 94 (26.9) | |||
Yes | 8 (18.2) | 36 (81.8) | 19 (44.2) | 24 (55.8) | 23 (52.3) | 21 (47.7) | |||
Total | 181 (45.8) | 214 (54.2) | <0.01 ‡ | 285 (73.8) | 101 (26.2) | <0.01 ‡ | 278 (70.7) | 115 (29.3) | 0.004 ‡ |
Diabetes mellitus | |||||||||
No | 168 (51.4) | 159 (48.6) | 252 (78.5) | 69 (21.5) | 248 (76.1) | 78 (23.9) | |||
Yes | 15 (19.5) | 62 (80.5) | 39 (53.4) | 34 (46.6) | 36 (47.4) | 40 (52.6) | |||
Total | 183 (45.3) | 221 (54.7) | <0.01 ‡ | 291 (73.9) | 103 (26.1) | <0.01 ‡ | 284 (70.6) | 118 (29.4) | <0.01 ‡ |
Severity § | |||||||||
Admission to critical care (n = 414) | |||||||||
No | 116 (51.8) | ||||||||
Yes | 108 (48.2) | ||||||||
Total | 224 (49.8) | <0.01 ‡ | |||||||
Ventilatory support required (n = 453) | |||||||||
No | 14 (6.2) | ||||||||
Yes | 213 (93.8) | ||||||||
Total | 227 (50.1) | <0.01 ‡ | |||||||
Death (n = 427) | |||||||||
No | 104 (45.4) | ||||||||
Yes | 125 (54.6) | ||||||||
Total | 229 (49.6) | <0.01 ‡ |
Gene | Variant | Genotype | Odds Ratio (OR) | 95% CI | p |
---|---|---|---|---|---|
IL1B | rs16944 | AA | 1.015 | 0.548–1.879 | 0.961 |
AG | 1.976 | 1.218–3.234 | 0.006 | ||
AA + AG vs. GG | 1.620 | 1.035–2.552 | 0.036 | ||
GG + AG vs. AA | 0.697 | 0.400–1.208 | 0.200 | ||
rs1143627 | TT | 0.958 | 0.526–1.745 | 0.887 | |
CT | 1.820 | 1.021–3.269 | 0.043 | ||
TT + CT vs. CC | 1.363 | 0.801–2.330 | 0.255 | ||
CC + CT vs. TT | 0.639 | 0.405–1.001 | 0.052 | ||
IL6 | rs2069845 | GG | 1.006 | 0.489–2.080 | 0.987 |
AG | 0.665 | 0.420–1.050 | 0.081 | ||
GG + AG vs. AA | 0.724 | 0.468–1.115 | 0.143 | ||
AA + AG vs. GG | 1.229 | 0.620–2.455 | 0.555 | ||
TNF | rs1799964 | CC | 1.720 | 0.684–4.422 | 0.252 |
CT | 1.970 | 1.220–3.215 | 0.006 | ||
CC + CT vs. TT | 1.927 | 1.226–3.060 | 0.005 | ||
TT + CT vs. CC | 1.364 | 0.554–3.426 | 0.501 | ||
rs1800630 | AA | 2.367 | 1.079–5.326 | 0.034 | |
AC | 1.584 | 0.919–2.681 | 0.101 | ||
AA + AC vs. CC | 1.755 | 1.094–2.842 | 0.021 | ||
CC + AC vs. AA | 2.112 | 0.976–4.687 | 0.061 | ||
rs1799724 | TT | 2.852 | 0.562–21.694 | 0.242 | |
CT | 1.411 | 0.823–2.434 | 0.212 | ||
TT + CT vs. CC | 1.491 | 0.886–2.529 | 0.134 | ||
CC + CT vs. TT | 2.654 | 0.524–20.149 | 0.275 | ||
rs1800629 | AA | 0.350 | 0.027–8.621 | 0.433 | |
AG | 1.054 | 0.606–1.833 | 0.852 | ||
AA + AG vs. GG | 1.020 | 0.590–1.762 | 0.944 | ||
GG + AG vs. AA | 0.347 | 0.027–8.530 | 0.429 |
Gene | Variant | Genotype | Odds Ratio (OR) | 95% CI | p |
---|---|---|---|---|---|
IL1B | rs16944 | AA | 0.835 | 0.452–1.559 | 0.567 |
AG | 1.834 | 1.092–3.101 | 0.022 | ||
AA + AG vs. GG | 1.425 | 0.891–2.272 | 0.138 | ||
GG + AG vs. AA | 0.608 | 0.349–1.077 | 0.083 | ||
rs1143627 | TT | 1.085 | 0.587–1.983 | 0.793 | |
CT | 2.082 | 1.123–3.848 | 0.019 | ||
TT + CT vs. CC | 1.526 | 0.873–2.626 | 0.131 | ||
CC + CT vs. TT | 0.669 | 0.418–1.073 | 0.094 | ||
IL6 | rs2069845 | GG | 1.590 | 0.715–3.852 | 0.276 |
AG | 0.653 | 0.400–1.061 | 0.086 | ||
GG + AG vs. AA | 0.776 | 0.485–1.233 | 0.285 | ||
AA + AG vs. GG | 1.979 | 0.934–4.630 | 0.091 | ||
TNF | rs1799964 | CC | 1.844 | 0.687–5.908 | 0.256 |
CT | 1.252 | 0.762–2.087 | 0.381 | ||
CC + CT vs. TT | 1.328 | 0.827–2.158 | 0.245 | ||
TT + CT vs. CC | 1.707 | 0.646–5.404 | 0.315 | ||
rs1800630 | AA | 1.474 | 0.651–3.689 | 0.376 | |
AC | 1.083 | 0.633–1.893 | 0.773 | ||
AA + AC vs. CC | 1.175 | 0.722–1.940 | 0.521 | ||
CC + AC vs. AA | 1.442 | 0.646–3.572 | 0.396 | ||
rs1799724 | TT | … | … | … | |
CT | … | … | … | ||
TT + CT vs. CC | 1.218 | 0.702–2.179 | 0.493 | ||
CC + CT vs. TT | … | … | … | ||
rs1800629 | AA | 0.568 | 0.025–6.342 | 0.654 | |
AG | 0.541 | 0.262–1.037 | 0.077 | ||
AA + AG vs. GG | 0.542 | 0.269–1.024 | 0.710 | ||
GG + AG vs. AA | 0.621 | 0.028–6.931 | 0.706 |
Gene | Variant | Genotype | Odds Ratio (OR) | 95% CI | p |
---|---|---|---|---|---|
IL1B | rs16944 | AA | 0.704 | 0.365–1.362 | 0.295 |
AG | 1.274 | 0.750–2.168 | 0.370 | ||
AA + AG vs. GG | 1.065 | 0.652–1.731 | 0.799 | ||
GG + AG vs. AA | 0.617 | 0.342–1.123 | 0.110 | ||
rs1143627 | TT | 1.357 | 0.709–2.590 | 0.354 | |
CT | 1.615 | 0.860–3.028 | 0.134 | ||
TT + CT vs. CC | 1.493 | 0.833–2.653 | 0.173 | ||
CC + CT vs. TT | 0.979 | 0.601–1.607 | 0.933 | ||
IL6 | rs2069845 | GG | 1.266 | 0.579–2.882 | 0.563 |
AG | 0.930 | 0.562–1.537 | 0.776 | ||
GG + AG vs. AA | 0.990 | 0.614–1.594 | 0.966 | ||
AA + AG vs. GG | 1.313 | 0.627–2.877 | 0.481 | ||
TNF | rs1799964 | CC | 3.728 | 1.208–14.366 | 0.034 |
CT | 1.452 | 0.863–2.479 | 0.165 | ||
CC + CT vs. TT | 1.658 | 1.008–2.766 | 0.049 | ||
TT + CT vs. CC | 3.279 | 1.081–12.472 | 0.052 | ||
rs1800630 | AA | 1.498 | 0.652–3.668 | 0.355 | |
AC | 1.619 | 0.904–2.973 | 0.112 | ||
AA + AC vs. CC | 1.583 | 0.945–2.700 | 0.086 | ||
CC + AC vs. AA | 1.328 | 0.587–3.205 | 0.509 | ||
rs1799724 | TT | … | … | … | |
CT | … | … | … | ||
TT + CT vs. CC | 1.682 | 0.931–3.141 | 0.092 | ||
CC + CT vs. TT | … | … | … | ||
rs1800629 | AA | 1.386 | 0.112–33.456 | 0.805 | |
AG | 1.033 | 0.550–1.895 | 0.918 | ||
AA + AG vs. GG | 1.047 | 0.566–1.898 | 0.880 | ||
GG + AG vs. AA | 1.379 | 0.111–33.228 | 0.808 |
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Feira, M.F.; Sbruzzi, R.C.; Maciel-Fiuza, M.F.; Griebeler, V.C.; Gregianini, T.S.; Martins, L.G.; Cadore, N.A.; Chies, J.A.B.; Kowalski, T.W.; Vianna, F.S.L. Association Between Genetic Variants in TNF, IL6, and IL1B Genes and Severity of COVID-19: A Cross-Sectional Study of Patients from Southern Brazil. Diagnostics 2025, 15, 1403. https://doi.org/10.3390/diagnostics15111403
Feira MF, Sbruzzi RC, Maciel-Fiuza MF, Griebeler VC, Gregianini TS, Martins LG, Cadore NA, Chies JAB, Kowalski TW, Vianna FSL. Association Between Genetic Variants in TNF, IL6, and IL1B Genes and Severity of COVID-19: A Cross-Sectional Study of Patients from Southern Brazil. Diagnostics. 2025; 15(11):1403. https://doi.org/10.3390/diagnostics15111403
Chicago/Turabian StyleFeira, Mariléa Furtado, Renan Cesar Sbruzzi, Miriãn Ferrão Maciel-Fiuza, Vitória Carolina Griebeler, Tatiana Schaffer Gregianini, Letícia Garay Martins, Nathan Araujo Cadore, Jose Artur Bogo Chies, Thayne Woycinck Kowalski, and Fernanda Sales Luiz Vianna. 2025. "Association Between Genetic Variants in TNF, IL6, and IL1B Genes and Severity of COVID-19: A Cross-Sectional Study of Patients from Southern Brazil" Diagnostics 15, no. 11: 1403. https://doi.org/10.3390/diagnostics15111403
APA StyleFeira, M. F., Sbruzzi, R. C., Maciel-Fiuza, M. F., Griebeler, V. C., Gregianini, T. S., Martins, L. G., Cadore, N. A., Chies, J. A. B., Kowalski, T. W., & Vianna, F. S. L. (2025). Association Between Genetic Variants in TNF, IL6, and IL1B Genes and Severity of COVID-19: A Cross-Sectional Study of Patients from Southern Brazil. Diagnostics, 15(11), 1403. https://doi.org/10.3390/diagnostics15111403