The Telomere-Telomerase System Is Detrimental to Health at High-Altitude
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Subjects
2.2. Ethics Approval
2.3. Estimation of Relative Telomere Length
2.4. Estimation of Telomerase Activity and Oxidative Stress Markers
2.5. Genotyping of Single Nucleotide Polymorphisms
2.6. Genetic Analyses
2.7. Gene-Gene Interactions in HAPE and Adaptation
2.8. DNA-Protein Docking
2.9. Protein-Protein Interactions
2.10. Expression Analysis of Telomere Maintaining Genes
2.11. Statistical Analyses
3. Results
3.1. Low SaO2 Indicates HAPE
3.2. Aberrant Telomere-Telomerase System Inclined with HAPE Susceptibility
3.3. The Oxidative System Shows Stronger Influence
3.4. Genetic Association with HAPE and HA Adaptation
3.5. Haplotypes Distribution Is Specific in HAPE and HA Adaptation
3.6. Gene-Gene Interactions
3.6.1. Best Interaction Models for HAPE
3.6.2. Best Interaction Models for HA Adaptation
3.7. Expression Profile Differed for Telomere Maintaining Genes
3.8. In Silico Analysis Underlined the Association of Decreased TERF2IP Expression with Risk Alleles in HAPE
3.9. Protein-Protein Interactions
3.10. Correlation between Biomarkers and Clinical Parameters
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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A. HAPE Risk/Protection | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Gene/ SNP | Genotype/ Allele | HAPE-f (n = 210) | HAPE-p (n = 183) | HLs (n = 200) | HAPE-p vs. HAPE-f | HLs vs. HAPE-f | HAPE-p vs. HLs | |||
p Value | OR (95%CI) | p Value | OR (95%CI) | p Value | OR (95%CI) | |||||
TERF2IP rs59297469 | GG | 73 (34.8%) | 40 (21.9%) | 138 (69.0%) | Ref | - | Ref | - | Ref | - |
GT | 105 (50.0%) | 92 (50.2%) | 57 (28.5%) | 0.575 | 1.17 (0.68–2.01) | 1.23 × 10−4 | 0.22 (0.10–0.47) | 1.00 × 10−10 | 8.48 (4.43–16.20) | |
TT | 32 (15.2%) | 51 (27.9%) | 5 (2.5%) | 0.037 | 1.98 (1.04–3.75) | 8.62 × 10−6 | 0.02 (0.004–0.12) | 1.03 × 10−8 | 69.64 (16.29–297.67) | |
G | 251 (59.8%) | 172 (47.0%) | 333 (83.2%) | Ref | - | Ref | - | Ref | - | |
T | 169 (40.2%) | 194 (53.0%) | 67 (16.8%) | 0.082 | 1.33 (0.96–1.83) | 2.25 × 10−9 | 0.16 (0.09–0.29) | 3.19 × 10−18 | 6.81 (4.42–10.49) | |
TERC rs2293607 | AA | 132 (62.8%) | 97 (53.0%) | 32 (16.0%) | Ref | - | Ref | - | Ref | - |
AG | 65 (31.0%) | 66 (36.1%) | 101 (50.5%) | 0.099 | 1.51 (0.93–2.47) | 1.30 × 10−6 | 9.04 (3.71–22.04) | 3.16 × 10−7 | 0.18 (0.10–0.35) | |
GG | 13 (6.2%) | 20 (10.9%) | 67 (33.5%) | 0.015 | 2.81 (1.22–6.46) | 8.04 × 10−9 | 26.92 (8.79–82.43) | 2.42 × 10−9 | 0.09 (0.04–0.19) | |
A | 329 (78.3%) | 260 (71.0%) | 165 (41.2%) | Ref | - | Ref | - | Ref | - | |
G | 91 (21.7%) | 106 (29.0%) | 235 (58.8%) | 0.005 | 1.70 (1.18–2.45) | 5.12 × 10−12 | 6.04 (3.62–10.06) | 6.81 × 10−12 | 0.27 (0.18–0.39) | |
TEP1 rs2228036 | GG | 134 (63.8%) | 95 (52.0%) | 127 (63.5%) | Ref | - | Ref | - | Ref | - |
GT | 69 (32.9%) | 72 (39.3%) | 57 (28.5%) | 0.581 | 1.15 (0.70–1.87) | 0.267 | 0.67 (0.32–1.37) | 0.040 | 1.77 (1.03–3.04) | |
TT | 7 (3.3%) | 16 (8.7%) | 16 (8.0%) | 0.042 | 2.84 (1.04–7.77) | 0.806 | 1.21 (0.26–5.65) | 0.406 | 1.48 (0.59–3.73) | |
G | 337 (80.2%) | 262 (71.6%) | 311 (77.8%) | Ref | - | Ref | - | Ref | - | |
T | 83 (19.8%) | 104 (28.4%) | 89 (22.2%) | 0.087 | 1.38 (0.95–2.01) | 0.447 | 0.80 (0.45–1.42) | 0.053 | 1.50 (0.99–2.27) | |
ACD rs72556537 | TT | 148 (70.4%) | 151 (82.5%) | 145 (72.5%) | Ref | - | Ref | - | Ref | - |
TA | 52 (24.8%) | 31 (17.0%) | 48 (24.0%) | 0.073 | 0.59 (0.34–1.05) | 0.138 | 0.53 (0.23–1.23) | 0.183 | 0.65 (0.34–1.23) | |
AA | 10 (4.8%) | 1 (0.5%) | 7 (3.5%) | 0.038 | 0.11 (0.01–0.88) | 0.346 | 1.89 (0.50–7.08) | 0.008 | 0.05 (0.01–0.45) | |
T | 348 (82.9%) | 333 (91.0%) | 338 (84.5%) | Ref | - | Ref | - | Ref | - | |
A | 72 (17.1%) | 33 (9.0%) | 62 (15.5%) | 0.003 | 0.48 (0.29–0.78) | 0.778 | 0.91 (0.49–1.71) | 0.002 | 0.43 (0.25–0.74) | |
B. HA Adaptation | ||||||||||
Gene/ SNP | Genotype/ Allele | HAPE-f (n = 210) | HAPE-p (n = 183) | HLs (n = 200) | HAPE-p vs. HAPE-f | HLs vs. HAPE-f | HAPE-p vs. HLs | |||
p Value | OR (95%CI) | p Value | OR (95%CI) | p Value | OR (95%CI) | |||||
TERF1 rs2975843 | TT | 76 (36.2%) | 61 (33.3%) | 112 (56.0%) | Ref | - | Ref | - | Ref | - |
TC | 97 (46.2%) | 82 (44.8%) | 81 (40.5%) | 0.729 | 0.91 (0.55–1.52) | 0.046 | 0.46 (0.22–0.99) | 0.033 | 1.82 (1.05–3.16) | |
CC | 37 (17.6%) | 40 (21.9%) | 7 (3.5%) | 0.806 | 1.08 (0.57–2.06) | 0.007 | 0.15 (0.04–0.60) | 2.98 × 10−5 | 9.07 (3.22–25.55) | |
T | 249 (59.3%) | 204 (55.7%) | 305 (76.2%) | Ref | - | Ref | - | Ref | - | |
C | 171 (40.7%) | 162 (44.3%) | 95 (23.8%) | 0.882 | 1.02 (0.74–1.42) | 0.003 | 0.46 (0.28–0.76) | 1.35 × 10−5 | 2.35 (1.60–3.45) | |
TERF1 rs10099824 | GG | 92 (43.8%) | 81 (44.3%) | 168 (84.0%) | Ref | - | Ref | - | Ref | - |
GA | 87 (41.4%) | 78 (42.6%) | 28 (14.0%) | 0.762 | 0.93 (0.56–1.53) | 5.52 × 10−6 | 0.06 (0.02–0.20) | 4.46 × 10−9 | 7.71 (3.90–15.27) | |
AA | 31 (14.8%) | 24 (13.1%) | 4 (2.0%) | 0.256 | 0.67 (0.33–1.34) | 4.49 × 10−5 | 0.02 (0.003–0.13) | 1.77 × 10−4 | 11.08 (3.15–38.96) | |
G | 271 (64.5%) | 240 (65.6%) | 364 (91.0%) | Ref | - | Ref | - | Ref | - | |
A | 149 (35.5%) | 126 (34.4%) | 36 (9.0%) | 0.285 | 0.83 (0.59–1.17) | 7.28 × 10−11 | 0.07 (0.03–0.15) | 7.05 × 10−12 | 5.96 (3.58–9.92) | |
TERF2 rs3785073 | GG | 99 (47.2%) | 76 (41.5%) | 108 (54.0%) | Ref | - | Ref | - | Ref | - |
GA | 83 (39.5%) | 86 (47.0%) | 80 (40.0%) | 0.864 | 1.04 (0.64–1.71) | 0.033 | 0.44 (0.20–0.94) | 0.001 | 2.64 (1.51–4.62) | |
AA | 28 (13.3%) | 21 (11.5%) | 12 (6.0%) | 0.899 | 0.96 (0.47–1.94) | 0.018 | 0.16 (0.03–0.73) | 0.070 | 2.70 (0.92–7.90) | |
G | 281 (66.9%) | 238 (65.0%) | 296 (74.0%) | Ref | - | Ref | - | Ref | - | |
A | 139 (33.1%) | 128 (35.0%) | 104 (26.0%) | 0.994 | 1.00 (0.71–1.40) | 0.002 | 0.43 (0.24–0.74) | 0.001 | 1.94 (1.30–2.90) | |
TERF2 rs153058 | TT | 129 (61.4%) | 107 (58.5%) | 92 (46.0%) | Ref | - | Ref | - | Ref | - |
TC | 73 (34.8%) | 65 (35.5%) | 84 (42.0%) | 0.680 | 1.11 (0.69–1.79) | 0.178 | 1.61 (0.80–3.24) | 0.047 | 0.58 (0.33–0.99) | |
CC | 8 (3.8%) | 11 (6.0%) | 24 (12.0%) | 0.164 | 2.07 (0.74–5.79) | 0.015 | 4.59 (1.35–15.63) | 0.015 | 0.31 (0.12–0.80) | |
T | 331 (78.8%) | 279 (76.2%) | 268 (67.0%) | Ref | - | Ref | - | Ref | - | |
C | 89 (21.2%) | 87 (23.8%) | 132 (33.0%) | 0.253 | 1.25 (0.85–1.82) | 0.014 | 1.89 (1.14–3.15) | 0.004 | 0.55 (0.37–0.83) | |
POT1 rs7794637 | CC | 90 (42.9%) | 63 (34.4%) | 105 (52.5%) | Ref | - | Ref | - | Ref | - |
CT | 95 (45.2%) | 88 (48.1%) | 82 (41.0%) | 0.682 | 0.90 (0.54–1.49) | 0.137 | 0.59 (0.29–1.19) | 0.003 | 2.30 (1.32–4.00) | |
TT | 25 (11.9%) | 32 (17.5%) | 13 (6.5%) | 0.297 | 1.43 (0.73–2.81) | 0.010 | 0.18 (0.05–0.66) | 0.003 | 4.22 (1.62–11.02) | |
C | 275 (65.5%) | 214 (58.5%) | 292 (73.0%) | Ref | - | Ref | - | Ref | - | |
T | 145 (34.5%) | 152 (41.5%) | 108 (27.0%) | 0.480 | 1.13 (0.81–1.57) | 0.010 | 0.51 (0.31–0.85) | 2.62 × 10−4 | 2.04 (1.39–2.99) | |
ACD rs6979 | GG | 67 (31.9%) | 54 (29.5%) | 18 (9.0%) | Ref | - | Ref | - | Ref | - |
GA | 110 (52.4%) | 101 (55.2%) | 74 (37.0%) | 0.828 | 1.06 (0.64–1.74) | 0.011 | 4.54 (1.41–14.62) | 0.334 | 0.68 (0.31–1.49) | |
AA | 33 (15.7%) | 28 (15.3%) | 108 (54.0%) | 0.982 | 1.01 (0.50–2.02) | 3.05 × 10−7 | 41.88 (10.03–174.91) | 3.74 × 10−8 | 0.07 (0.03–0.18) | |
G | 244 (58.1%) | 209 (57.1%) | 110 (27.5%) | Ref | - | Ref | - | Ref | - | |
A | 176 (41.9%) | 157 (42.9%) | 290 (72.5%) | 0.844 | 1.03 (0.75–1.43) | 3.34 × 10−12 | 7.34 (4.19–12.86) | 5.62 × 10−12 | 0.26 (0.18–0.38) | |
TEP1 rs2184282 | AA | 138 (65.7%) | 134 (73.2%) | 97 (48.5%) | Ref | - | Ref | - | Ref | - |
AG | 58 (27.6%) | 41 (22.4%) | 69 (34.5%) | 0.108 | 0.64 (0.37–1.10) | 0.015 | 2.43 (1.18–4.97) | 0.002 | 0.39 (0.22–0.70) | |
GG | 14 (6.7%) | 8 (4.4%) | 34 (17.0%) | 0.550 | 0.74 (0.27–2.01) | 0.004 | 4.60 (1.63–12.95) | 2.38 × 10−5 | 0.11 (0.04–0.31) | |
A | 334 (79.5%) | 309 (84.4%) | 263 (65.8%) | Ref | - | Ref | - | Ref | - | |
G | 86 (20.5%) | 57 (15.6%) | 137 (34.2%) | 0.128 | 0.72 (0.47–1.10) | 2.95 × 10−4 | 2.52 (1.53–4.16) | 7.81 × 10−8 | 0.31 (0.20–0.47) | |
TEP1 rs4246977 | TT | 57 (27.1%) | 45 (24.6%) | 127 (63.5%) | Ref | - | Ref | - | Ref | - |
TC | 105 (50.0%) | 99 (54.1%) | 60 (30.0%) | 0.493 | 1.21 (0.70–2.11) | 2.88 × 10−4 | 0.22 (0.10–0.50) | 8.99 × 10−7 | 4.20 (2.37–7.44) | |
CC | 48 (22.9%) | 39 (21.3%) | 13 (6.5%) | 0.525 | 0.81 (0.42–1.56) | 4.58 × 10−5 | 0.09 (0.03–0.28) | 8.50 × 10−6 | 6.76 (2.92–15.69) | |
T | 219 (52.1%) | 189 (51.6%) | 314 (78.5%) | Ref | - | Ref | - | Ref | - | |
C | 201 (47.9%) | 177 (48.4%) | 86 (21.5%) | 0.538 | 0.90 (0.66–1.25) | 2.68 × 10−7 | 0.25 (0.15–0.42) | 1.35 × 10−8 | 3.08 (2.09–4.54) |
Gene | Haplotype | HAPE-p vs. HAPE-f | HLs vs. HAPE-f | HAPE-p vs. HLs | ||||||
---|---|---|---|---|---|---|---|---|---|---|
χ2 | OR (95% CI) | p-Value | χ2 | OR (95% CI) | p-Value | χ2 | OR (95% CI) | p-Value | ||
TERF1 | AAGG | 0.927 | 1.17 (0.85–1.63) | 0.336 | 18.700 | 2.84 (1.77–4.56) | 1.53 × 10−5 | 22.768 | 0.41 (0.29–0.59) | 1.83 × 10−6 |
GAAA * | 5.190 | 0.58 (0.37–0.93) | 0.023 | 10.145 | 0.22 (0.09–0.56) | 0.001 | 4.581 | 2.18 (1.07–4.44) | 0.032 | |
TPP1 + TERF2 + RAP1 | AAAAATTCGCA | 6.133 | 4.71 (1.38–16.06) | 0.013 | 7.470 | 0.05 (0.01–0.43) | 0.006 | |||
AAGTATCCGCA | 1.369 | 0.66 (0.33–1.33) | 0.242 | 6.893 | 2.42 (1.25–4.67) | 0.009 | 12.218 | 0.37 (0.22–0.65) | 4.73 × 10−4 | |
AAGTATTCGCA | 11.734 | 5.49 (2.07–14.55) | 0.001 | 12.983 | 0.14 (0.05–0.41) | 3.14 × 10−4 | ||||
AAGTGTCCGCA | 2.512 | 1.77 (0.87–3.57) | 0.113 | 16.480 | 4.44 (2.16–9.12) | 4.92 × 10−5 | 19.034 | 0.29 (0.17–0.51) | 1.28 × 10−5 | |
TGGTATCCGCA | 0.701 | 0.63 (0.21–1.87) | 0.402 | 5.101 | 3.60 (1.18–10.93) | 0.024 | ||||
TERT | GATCGCCAG | 1.308 | 0.72 (0.41–1.26) | 0.253 | 22.883 | 3.75 (2.18–6.44) | 1.72 × 10−6 | 38.560 | 0.23 (0.15–0.37) | 5.31 × 10−10 |
TEP1 + HSP90AA1 | TCCCGACTTA * | 6.003 | 0.23 (0.07–0.74) | 0.014 | 0.043 | 0.89 (0.30–2.63) | 0.835 | |||
TCCCGGCTCA | 1.063 | 1.74 (0.61–4.97) | 0.303 | 4.621 | 4.40 (1.14–16.98) | 0.032 | 1.215 | 0.58 (0.22–1.52) | 0.270 | |
TTCCGATCT * | 8.066 | 0.18 (0.05–0.58) | 0.005 | |||||||
TTCCGGCTCA | 4.482 | 5.58 (1.14–27.44) | 0.034 | 7.513 | 0.25 (0.09–0.68) | 0.006 |
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Pasha, Q.; Rain, M.; Tasnim, S.; Kanipakam, H.; Thinlas, T.; Mohammad, G. The Telomere-Telomerase System Is Detrimental to Health at High-Altitude. Int. J. Environ. Res. Public Health 2023, 20, 1935. https://doi.org/10.3390/ijerph20031935
Pasha Q, Rain M, Tasnim S, Kanipakam H, Thinlas T, Mohammad G. The Telomere-Telomerase System Is Detrimental to Health at High-Altitude. International Journal of Environmental Research and Public Health. 2023; 20(3):1935. https://doi.org/10.3390/ijerph20031935
Chicago/Turabian StylePasha, Qadar, Manjari Rain, Sana Tasnim, Hema Kanipakam, Tashi Thinlas, and Ghulam Mohammad. 2023. "The Telomere-Telomerase System Is Detrimental to Health at High-Altitude" International Journal of Environmental Research and Public Health 20, no. 3: 1935. https://doi.org/10.3390/ijerph20031935