Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. SNP Selection
2.3. SNP Genotyping
2.4. ELISA for Serum Cytokine Measurement
2.5. Statistical Analysis
2.6. SNP Targeted Pathway Analysis
3. Results
3.1. The Study Population Was Devoid of Population Stratification
3.2. Cytokine Genetic Variants Show Significant Allelic and Haplotypic Association in PTB and Not in LNTB
3.3. Gene-Gene Epistatic Interaction Analysis Reveals a Higher Risk for Cytokine Genes Majorly in PTB and Not LNTB
3.4. Lack of Major Association of Cytokine Levels with Genotypes in LNTB
3.5. Innate Immunity Related Genes Are Majorly Associated with LNTB and Not PTB
3.6. Pathway Analysis Reveals an Apoptotic Axis for LNTB and a Cytokine Axis for PTB
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 | SNP (rsID) | Risk Allele | Case, Control Frequencies | Odds Ratio (CI) | p-Value | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
PTB (n = 110) | LNTB (n = 35) | Combined (n = 145) | PTB | LNTB | Combined | PTB | LNTB | Combined | |||
TNFB | rs746868 | C/C/C | 0.650, 0.543 | 0.589, 0.543 | 0.637, 0.543 | 1.6 (1.0–2.4) | NA | NA | 0.0442 | 0.5545 | 0.0647 |
IL10 | rs1878672 | C/G/C | 0.937, 0.812 | 0.250, 0.188 | 0.894, 0.812 | 3.4 (1.6–7.2) | NA | 2.0 (1.1–3.6) | 0.0007 | 0.3487 | 0.0271 |
IL1B | rs1143643 | G/A/G | 0.935, 0.817 | 0.286, 0.183 | 0.887, 0.817 | 3.2 (1.6–6.6) | NA | NA | 0.001 | 0.1174 | 0.0635 |
IL1RA | rs419598 | C/T/C | 0.418, 0.264 | 0.796, 0.736 | 0.369, 0.264 | 2 (1.2–3.4) | NA | NA | 0.0079 | 0.401 | 0.054 |
IL6 | rs1548216 | G/C/C | 0.985, 0.978 | 0.089, 0.022 | 0.031, 0.022 | NA | 4.4 (1.0–19) | NA | 0.6447 | 0.032 | 0.5846 |
Gene | Block | Haplotype | Case, Control Frequencies | p-Value | ||||||
---|---|---|---|---|---|---|---|---|---|---|
PTB | LNTB | Combined | PTB | LNTB | Combined | PTB | LNTB | Combined | ||
IL18 | Block 1 | |||||||||
TG | 0.907 | 0.884 | 0.905 | 0.926, 0.880 | 0.893, 0.880 | 0.919, 0.880 | 0.153 | 0.8036 | 0.211 | |
CC | 0.093 | 0.116 | 0.095 | 0.074, 0.120 | 0.107, 0.120 | 0.081, 0.120 | 0.153 | 0.8036 | 0.211 | |
TNFB | Block 2 | |||||||||
GC/GCC | 0.609 | 0.281 | 0.601 | 0.650, 0.549 | 0.313, 0.268 | 0.629, 0.548 | 0.0568 | 0.5305 | 0.1146 | |
TG/GTC | 0.383 | 0.269 | 0.387 | 0.343, 0.441 | 0.241, 0.280 | 0.358, 0.442 | 0.0637 | 0.5736 | 0.098 | |
TTC | 0.011 | 0.036, 0.001 | 0.0303 | |||||||
TTG | 0.433 | 0.411, 0.442 | 0.6911 |
Gene | SNP (rsID) | Risk Allele | Case, Control Frequencies | Odds Ratio (CI) | p-Value | P-Bonferroni | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PTB | LNTB | Combined | PTB | LNTB | Combined | PTB | LNTB | Combined | PTB | LNTB | Combined | |||
IFNG | rs1861493 | A | 0.935, 0.858 | 0.148, 0.142 | 0.912, 0.858 | 2.4 (1.3 –4.2) | 1.1 (0.62–1.8) | 1.7 (1.1–2.7) | 0.002 | 0.853 | 0.0197 | 0.013 | 1 | 0.138 |
IL1RA | rs4252019 | C | 0.974, 0.934 | 0.090, 0.066 | 0.962, 0.934 | 2.6 (1.1–6.0) | 1.4 (0.72–2.7) | 1.8 (0.93–3.4) | 0.018 | 0.314 | 0.078 | 0.159 | 1 | 0.71 |
IL4 | rs2070874 | T | 0.306, 0.239 | 0.847, 0.761 | 0.280, 0.239 | 1.4 (1.0–2.0) | 1.7 (1.1–2.9) | 1.2 (0.90–1.7) | 0.048 | 0.027 | 0.194 | 0.303 | 0.2436 | 1 |
IL12 | rs2853694 | A | 0.624, 0.508 | 0.620, 0.508 | 0.608, 0.508 | 1.6 (1.2–2.2) | 1.6 (1.1–2.3) | 1.5 (1.1–2.0) | 0.002 | 0.018 | 0.004 | 0.017 | 0.1624 | 0.032 |
rs3212220 | T | 0.409, 0.297 | 0.355, 0.297 | 0.394, 0.297 | 1.6 (1.2–2.2) | 1.3 (0.8–1.9) | 1.5 (1.2–2.1) | 0.002 | 0.186 | 0.003 | 0.017 | 1 | 0.031 |
CHR1 | Gene | SNP1 | CHR2 | Gene | SNP2 | OR_INT | STAT | p-Value | TB Form |
---|---|---|---|---|---|---|---|---|---|
2 | IL1RA | rs1794068 | 2 | IL1RA | rs3213448 | 0.07834 | 21.47 | 3.60 × 10−6 | PTB |
2 | IL1RA | rs1794068 | 2 | IL1RA | rs3181052 | 0.08759 | 22.68 | 1.92 × 10−6 | PTB |
2 | IL1RA | rs1794068 | 5 | IL12 | rs3213119 | 0.04328 | 24.7 | 6.69 × 10−7 | PTB |
2 | IL1RA | rs1794068 | 5 | IL12 | rs3213096 | 0.06435 | 25.68 | 4.03 × 10−7 | PTB |
2 | IL1RA | rs1794068 | 6 | TNFB | rs3093542 | 0.05699 | 26.41 | 2.76 × 10−7 | PTB |
2 | IL1RA | rs315951 | 2 | IL1RA | rs9005 | 8.265 | 17.38 | 3.07 × 10−5 | PTB |
2 | IL1RA | rs315951 | 5 | IL4 | rs2243266 | 0.1028 | 17.66 | 2.64 × 10−5 | PTB |
2 | IL1RA | rs315951 | 5 | IL12 | rs3213119 | 0.008753 | 31.27 | 2.25 × 10−8 | PTB |
2 | IL1RA | rs315951 | 5 | IL12 | rs3213096 | 0.007691 | 32.86 | 9.92 × 10−9 | PTB |
2 | IL1RA | rs315951 | 6 | TNFB | rs3093542 | 0.008263 | 32.32 | 1.31 × 10−8 | PTB |
5 | IL4 | rs2070874 | 5 | IL12 | rs3213119 | 18.18 | 29.85 | 4.66 × 10−8 | PTB |
5 | IL4 | rs2070874 | 5 | IL12 | rs3213096 | 18.33 | 30.69 | 3.03 × 10−8 | PTB |
5 | IL4 | rs2070874 | 6 | TNFB | rs3093542 | 18.86 | 31.75 | 1.76 × 10−8 | PTB |
5 | IL4 * | rs2070874 | 5 | IL12 | rs3213096 | 16.71 | 37.64 | 8.52 × 10−10 | PTB |
5 | IL4 * | rs2070874 | 5 | IL12 | rs730690 | 5.056 | 16.02 | 6.26 × 10−5 | PTB |
5 | IL4 * | rs2070874 | 5 | IL4 | rs2243266 | 5.007 | 23.61 | 1.18 × 10−6 | LNTB |
Gene | db SNP rsID/Other Name | Gene Location | Risk Allele | Case, Control Frequencies | Chi Square | p-Value | Odds Ratio | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
(CI) | |||||||||||
PTB | LNTB | PTB | LNTB | PTB | LNTB | PTB | LNTB | ||||
P2RX7 | rs2393799/−762T/C | Exon | C | 0.707, 0.611 | 0.917, 0.611 | 3.892 | 19.23 | 0.048 | 1.15 × 10−5 | 1.5 (1–2.4) | 7 (2.6–18.4) |
rs3751143/1513 A/C | Exon | C | 0.574, 0.525 | 0.574, 0.525 | 0.816 | 0.079 | 0.3664 | 0.7791 | 1.2 (0.79–1.7) | 1.1 (0.5–2.2) | |
VDR | rs2228570/FokI | Exon | G | 0.505, 0.472 | 0.552, 0.472 | 0.436 | 1.151 | 0.5 | 0.288 | ND | ND |
rs731236/TaqI | Exon | C | 0.893, 0.861 | 0.895, 0.525 | 0.849 | 0.298 | 0.357 | 0.5849 | ND | ND | |
rs1544410/BsmI | Exon | Only GG Genotype observed | |||||||||
IRGM | rs9637876/−261T/C | Alu sequence | C | 0.306, 0.255 | 0.272, 0.255 | 1.53 | 1.2 | 0.2161 | 0.515 | ND | ND |
TLR2 | rs6265786/Arg 299 Trp | intron | G | 1.000, 0.958 | 0.979, 0.958 | 9.53 | 0.471 | 0.002 | 0.4925 | 20.92 (1.2–369.3) | 2.1 (0.25–17.25) |
TLR4 | rs498670/Asp 299 Gly | Intron | G | 0.223, 0.125 | 0.05, 0.125 | 6.09 | 2.622 | 0.0135 | 0.1054 | 2.1 (1.2–2.5) | 0.11 (0.10–1.3) |
NOS2A | rs7215373 | Intron | T | 0.481, 0.405 | 0.514, 0.400 | 2.732 | 2.914 | 0.0983 | 0.0878 | 1.3 (0.94–1.95) | 1.6 (0.94–2.65) |
rs2274894 | 3’UTR | T/G | 0.213, 0.171 | 0.05, 0.125 | 1.348 | 0.45 | 0.2456 | 0.5022 | 1.3 (0.83–2.06) | 1.3 (0.63–2.6) | |
SLC11A1/NRAMP1 | rs3731865 | Exon | Only CC genotype observed | ||||||||
17235409 | Intron | Only AG genotype observed | |||||||||
SP110 | rs6436915 | Intron | T | 0.421, 0.347 | 0.417, 0.350 | 2.766 | 1.038 | 0.0963 | 0.3082 | ND | ND |
rs1346311 | Intron | T | 0.105, 0.104 | 0.959, 0.900 | 0.001 | 2.516 | 0.9701 | 0.1127 | ND | ND | |
rs7580900 | Intron | T | 0.531, 0.473 | 0.554, 0.472 | 1.613 | 1.471 | 0.204 | 0.2252 | ND | ND | |
DCSIGN (CD209) | rs4804803/−336 A/G | Promoter | A | 0.745, 0.380 | 0.534, 0.380 | 55.47 | 4.52 | 9.48 × 10−14 | 3.34 × 10−2 | 4.0 (2.6–6.0) | 1.9 (1.0–3.4) |
SNP | Groups | N | Genotype Frequencies | Allele Frequencies | Without Heterozygosity Model | Heterozygosity Model | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
(01 vs. 00 + 11) | ||||||||||||
00 | 01 | 11 | 0 | 1 | OR (CI ) | p-Value | OR (CI) | p-Value | Padj | |||
rs1978331 | All TB | 185 | 0.26 | 0.44 | 0.30 | 0.48 | 0.52 | 1.02 (0.73–1.41) | 0.9209 | 0.55 (0.34–0.87) | 0.013 | 0.039 |
T = 0, C = 1 | PTB | 135 | 0.25 | 0.46 | 0.29 | 0.48 | 0.52 | 1 (0.70–1.43) | 0.9738 | 0.60 (0.36–0.99) | 0.076 | 0.168 |
LNTB | 50 | 0.3 | 0.38 | 0.32 | 0.49 | 0.51 | 1.04 (0.65–1.66) | 0.8533 | 0.43 (0.22–0.85) | 0.018 | 0.037 | |
Control | 120 | 0.18 | 0.59 | 0.23 | 0.47 | 0.52 | ||||||
rs2660898 | TT | TG | GG | |||||||||
T = 0, G = 1 | All TB | 185 | 0.17 | 0.41 | 0.42 | 0.38 | 0.63 | 1.21 (0.85–1.7) | 0.2761 | 0.76(0.48–1.2) | 0.283 | 0.849 |
PTB | 135 | 0.15 | 0.42 | 0.44 | 0.36 | 0.64 | 1.1 (0.76–1.61) | 0.5822 | 0.77(0.46–1.3) | 0.309 | 0.927 | |
LNTB | 50 | 0.22 | 0.4 | 0.36 | 0.43 | 0.57 | 1.5(0.93–2.44) | 0.093 | 0.75(0.38–1.5) | 0.496 | 1.488 | |
Control | 120 | 0.09 | 0.48 | 0.43 | 0.33 | 0.67 | ||||||
TT | TC | CC | ||||||||||
rs17525495 | All TB | 185 | 0.06 | 0.24 | 0.69 | 0.19 | 0.82 | 1.33(0.83–2.1) | 0.238 | 0.95(0.53–1.7) | 0.8827 | 2.6481 |
T = 0, C = 1 | PTB | 135 | 0.05 | 0.25 | 0.65 | 0.19 | 0.81 | 1.31(0.78–2.2) | 0.298 | 1.1(0.60–2.1) | 0.753 | 2.259 |
LNTB | 50 | 0.08 | 0.18 | 0.62 | 0.19 | 0.80 | 1.38(0.72–2.65) | 0.329 | 0.82(0.35–1.9) | 0.831 | 2.493 | |
Control | 120 | 0.03 | 0.24 | 0.73 | 0.15 | 0.85 |
db SNP rsID | Risk Allele | Males (Case = 75; Control = 70) | Female (Case = 50; Control = 54) | ||||||
---|---|---|---|---|---|---|---|---|---|
Case, Control Frequencies | p-Value | P Bonferroni | Odds Ratio (CI) | Case, Control Frequencies | p-Value | P Bonferroni | Odds Ratio (CI) | ||
rs3788935 | A | 0.1102, 0.01 | 0.0072 | 0.0288 | 17 (0.94–300) | 0.160, 0.106 | 0.1673 | 0.6692 | 1.6 (0.82–3.2) |
rs3761624 | A | 0.2, 0.05 | 0.012 | 0.048 | 4.3 (1.2–16) | 0.356, 0.244 | 0.0423 | 0.1692 | 1.7 (1.0–2.9) |
rs3764880 | A | 0.107, 0.029 | 0.1012 | 0.4048 | 3.9 (0.81–19) | 0.229, 0.149 | 0.0557 | 0.2228 | 1.7 (0.98–2.9) |
rs3764879 | C | 0.558, 0.482 | 0.5934 | 2.3736 | 1.3 (0.61–2.6) | 0.489, 0.440 | 0.3981 | 1.5924 | 1.2 (0.77–1.9) |
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Abhimanyu; Bose, M.; Giri, A.; Varma-Basil, M. Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis. Genes 2023, 14, 207. https://doi.org/10.3390/genes14010207
Abhimanyu, Bose M, Giri A, Varma-Basil M. Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis. Genes. 2023; 14(1):207. https://doi.org/10.3390/genes14010207
Chicago/Turabian StyleAbhimanyu, Mridula Bose, Astha Giri, and Mandira Varma-Basil. 2023. "Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis" Genes 14, no. 1: 207. https://doi.org/10.3390/genes14010207
APA StyleAbhimanyu, Bose, M., Giri, A., & Varma-Basil, M. (2023). Comparative Genetic Association Analysis of Human Genetic Susceptibility to Pulmonary and Lymph Node Tuberculosis. Genes, 14(1), 207. https://doi.org/10.3390/genes14010207