Introduction
Materials and methods
Study design and enrollment
Single nucleotide polymorphism selection and genotyping
Isolation and stimulation of cells from healthy subjects
RNA purification and tissue factor mRNA expression analysis
Serum collection and tissue factor level measurement
Statistical analysis
Results
Characteristics of the study population
Sepsis patients | Severe sepsis patients | P value a | Survivors | Nonsurvivors | P value b | |
---|---|---|---|---|---|---|
Number | 577 | 476 | NA | 308 | 168 | NA |
Age | 62.6 ± 11.2 | 66.1 ± 11.5 | 0.07 | 62.6 ± 10.8 | 68.9 ± 13.7 | 0.04 |
Sex (male/female) | 334/243 | 275/201 | 0.56 | 180/128 | 98/70 | 0.98 |
APACHE II score | 10.4 ± 3.3 | 18.7 ± 4.8 | 0.007 | 14.6 ± 2.8 | 26.2 ± 7.1 | 0.008 |
Diabetes | 50 (8.7%) | 51 (10.7%) | 0.26 | 33 (10.7%) | 18 (10.7%) | 1.00 |
Chronic liver disease | 11 (1.9%) | 17 (3.6%) | 0.10 | 9 (2.9%) | 8 (4.8%) | 0.30 |
Chronic renal failure | 18 (3.1%) | 20 (4.2%) | 0.35 | 12 (3.9%) | 8 (4.8%) | 0.65 |
Congestive heart failure | 25 (4.3%) | 32 (6.7%) | 0.09 | 20 (6.5%) | 12 (7.1%) | 0.79 |
Chronic pulmonary disease | 35 (6.1%) | 42 (8.8%) | 0.09 | 25 (8.1%) | 17 (10.1%) | 0.46 |
SOFA score | 1.4 ± 0.3 | 8.1 ± 1.7 | <0.001 | 6.8 ± 1.8 | 10.5 ± 1.8 | 0.01 |
LOS (days) | 8.5 ± 2.6 | 15.3 ± 8.6 | 0.006 | 13.5 ± 7.3 | 15.1 ± 8.9 | 0.02 |
Infection insult | ||||||
Lung | 380 (65.9%) | 312 (65.5%) | 0.92 | 206 (66.9%) | 106 (63.1%) | 0.41 |
Abdomen | 151 (26.2%) | 119 (25.0%) | 0.67 | 73 (23.7%) | 46 (27.4%) | 0.38 |
Bloodstream | 13 (2.3%) | 17 (3.6%) | 0.20 | 8(2.6%) | 9 (5.4%) | 0.12 |
UTI | 11 (1.9%) | 12 (2.5%) | 0.50 | 9 (2.9%) | 3 (1.8%) | 0.45 |
Others | 22 (3.8%) | 16 (3.4%) | 0.70 | 12 (3.9%) | 4 (2.4%) | 0.38 |
Microbiology positivec | 225 (39.0%) | 195 (41.0%) | 0.52 | 114 (37.0%) | 76 (45.2%) | 0.08 |
Gram-positive | 96 (42.7%) | 75 (38.5%) | 0.38 | 47 (41.2%) | 27 (35.5%) | 0.43 |
Gram-negative | 98 (43.6%) | 81 (41.5%) | 0.68 | 47 (41.2%) | 31 (40.8%) | 0.95 |
Fungi | 15 (6.7%) | 18 (9.2%) | 0.33 | 10 (8.8%) | 8 (10.5%) | 0.69 |
Mixed | 16 (7.1%) | 21 (10.8%) | 0.19 | 10 (8.8%) | 10 (13.2%) | 0.34 |
Association analyses of TF and TFPIpolymorphisms with susceptibility to severe sepsis
Gene | Sepsis | Severe sepsis | Allelic comparison | Genotypic comparison | ||||
---|---|---|---|---|---|---|---|---|
SNP | patients | patients | P 1adj | OR 1adj (95% CI) | P 2adj | OR 2adj (95% CI) | P 1adj | P 2adj |
TF
| ||||||||
rs1324214 | 0.13 | 0.86 (0.71 to 1.05) | 0.22 | 0.89 (0.83 to 1.04) | 0.09 | 0.14 | ||
CC | 270 (47.8%) | 253 (54.2%) | ||||||
CT | 270 (47.8%) | 191 (40.9%) | ||||||
TT | 25 (4.4%) | 23 (4.9%) | ||||||
T | 810 (71.7%) | 697 (74.6%) | ||||||
C | 320 (28.3%) | 237 (25.4%) | ||||||
rs762484 | 0.22 | 0.86 (0.69 to 1.09) | 0.36 | 0.89 (0.74 to 1.07) | 0.07 | 0.12 | ||
TT | 374 (66%) | 330 (71%) | ||||||
TC | 185 (32.6%) | 124 (26.7%) | ||||||
CC | 8 (1.4%) | 11 (2.4%) | ||||||
T | 933 (82.3%) | 784 (84.3%) | ||||||
C | 201 (17.7%) | 146 (15.7%) | ||||||
rs696619 | 0.31 | 0.91 (0.76 to 1.09) | 0.46 | 0.93 (0.79 to 1.06) | 0.14 | 0.26 | ||
AA | 228 (40.7%) | 192 (41.5%) | ||||||
AG | 271 (48.4%) | 237 (51.2%) | ||||||
GG | 61 (10.9%) | 34 (7.3%) | ||||||
A | 727 (64.9%) | 621 (67.1%) | ||||||
G | 393 (35.1%) | 305 (32.9%) | ||||||
rs3917615 | 0.87 | 0.98 (0.80 to 1.21) | 0.92 | 0.98 (0.83 to 1.18) | 0.07 | 0.16 | ||
CC | 344 (61.3%) | 280 (59.5%) | ||||||
CT | 189 (33.7%) | 179 (38%) | ||||||
TT | 28 (5%) | 12 (2.5%) | ||||||
C | 877 (78.2%) | 739 (78.5%) | ||||||
T | 245 (21.8%) | 203 (21.5%) | ||||||
rs1361600 | 0.53 | 0.94 (0.76 to 1.15) | 0.72 | 0.95 (0.82 to 1.12) | 0.07 | 0.16 | ||
AA | 342 (60%) | 280 (59.6%) | ||||||
AG | 198 (34.7%) | 178 (37.9%) | ||||||
GG | 30 (5.3%) | 12 (2.6%) | ||||||
A | 882 (77.4%) | 738 (78.5%) | ||||||
G | 258 (22.6%) | 202 (21.5%) | ||||||
rs958587 | 0.62 | 0.95 (0.77 to 1.17) | 0.78 | 0.96 (0.84 to 1.14) | 0.06 | 0.15 | ||
CC | 342 (60.4%) | 279 (59.4%) | ||||||
CT | 194 (34.3%) | 178 (38.0%) | ||||||
TT | 30 (5.3%) | 12 (2.6%) | ||||||
C | 878 (77.6%) | 736 (78.5%) | ||||||
T | 254 (22.4%) | 202 (21.5%) | ||||||
rs3917643 | 1.00 | 0.22 (0.25 to 6.05) | 0.85 | 0.29 (0.32 to 5.26) | 1.00 | 0.98 | ||
AA | 570 (99.5%) | 468 (99.4%) | ||||||
AG | 3 (0.5%) | 3 (0.6%) | ||||||
A | 1143 (99.7%) | 939 (99.7%) | ||||||
G | 3 (0.3%) | 3 (0.3%) | ||||||
rs145977586 | 1.00 | 0.22 (0.25 to 6.05) | 0.85 | 0.29 (0.32 to 5.26) | 1.00 | 0.98 | ||
GG | 570 (99.5%) | 468 (99.4%) | ||||||
GA | 3 (0.5%) | 3 (0.6%) | ||||||
G | 1143 (99.7%) | 939 (99.7%) | ||||||
A | 3 (0.3%) | 3 (0.3%) | ||||||
TFPI
| ||||||||
rs3755248 | 0.75 | 0.96 (0.75 to 1.23) | 0.67 | 0.87 (0.71 to 1.18) | 0.71 | 0.62 | ||
TT | 412 (73%) | 342 (73.4%) | ||||||
TC | 141 (25%) | 118 (25.3%) | ||||||
CC | 11 (2%) | 6 (12.9%) | ||||||
T | 965 (85.5%) | 802 (86.1%) | ||||||
C | 163 (14.5%) | 130 (13.9%) | ||||||
rs3213739 | 0.46 | 1.07 (0.90 to 1.28) | 0.32 | 1.15 (0.82 to 1.32) | 0.79 | 0.56 | ||
GG | 270 (47.7%) | 218 (46.4%) | ||||||
GT | 156 (27.6%) | 127 (27%) | ||||||
TT | 140 (24.7%) | 125 (26.6%) | ||||||
G | 696 (61.5%) | 563 (59.9%) | ||||||
T | 436 (38.5%) | 377 (40.1%) | ||||||
rs7594359 | 0.93 | 0.99 (0.78 to 1.25) | 0.94 | 0.94 (0.79 to 1.18) | 0.12 | 0.17 | ||
CC | 389 (69.5%) | 317 (68.2%) | ||||||
CT | 156 (27.9%) | 143 (30.8%) | ||||||
TT | 15 (2.7%) | 5 (1.1%) | ||||||
C | 934 (83.4%) | 777 (83.5%) | ||||||
T | 186 (16.6%) | 153 (16.5%) | ||||||
rs10931292 | 0.92 | 0.99 (0.82 to 1.19) | 0.82 | 0.78 (0.76 to 1.12) | 0.14 | 0.12 | ||
TT | 255 (44.9%) | 222 (47.9%) | ||||||
TC | 253 (44.5%) | 180 (38.9%) | ||||||
CC | 60 (10.6%) | 61 (13.2%) | ||||||
T | 763 (67.2%) | 624 (67.4%) | ||||||
C | 373 (32.8%) | 302 (32.6%) | ||||||
rs8176441 | 0.93 | 0.99 (0.81 to 1.21) | 0.82 | 0.76 (0.56 to 1.48) | 0.10 | 0.23 | ||
TT | 300 (52.9%) | 259 (55.7%) | ||||||
TC | 237 (41.8%) | 170 (36.6%) | ||||||
CC | 30 (5.3%) | 36 (7.7%) | ||||||
T | 837 (73.8%) | 688 (74%) | ||||||
C | 297 (26.2%) | 242 (26%) | ||||||
rs12613071 | 0.84 | 1.02 (0.84 to 1.23) | 0.75 | 1.24 (0.86 to 1.38) | 0.98 | 0.95 | ||
TT | 288 (50.9%) | 233 (50.2%) | ||||||
TC | 224 (39.6%) | 186 (40.1%) | ||||||
CC | 54 (9.5%) | 45 (9.7%) | ||||||
T | 800 (70.7%) | 652 (70.3%) | ||||||
C | 332 (29.3%) | 276 (29.7%) | ||||||
rs10153820 | 0.58 | 0.95 (0.79 to 1.14) | 0.62 | 0.98 (0.81 to 1.12) | 0.15 | 0.36 | ||
GG | 254 (45.3%) | 230 (49.4%) | ||||||
GA | 251 (44.7%) | 181 (38.8%) | ||||||
AA | 56 (10%) | 55 (11.8%) | ||||||
G | 759 (67.6%) | 641 (68.8%) | ||||||
A | 363 (32.4%) | 291 (31.2%) | ||||||
rs8176592 | 0.12 | 1.24 (0.94 to 1.63) | 0.36 | 1.16 (0.97 to 1.58) | 0.31 | 0.45 | ||
TT | 461 (80.9%) | 363 (77.1%) | ||||||
TC | 102 (17.9%) | 100 (21.2%) | ||||||
CC | 7 (1.2%) | 8 (1.7%) | ||||||
T | 1024 (89.8%) | 826 (87.7%) | ||||||
C | 116 (10.2%) | 116 (12.3%) | ||||||
rs2192824 | 0.79 | 1.03 (0.83 to 1.27) | 0.65 | 1.13 (0.92 to 1.46) | 0.76 | 0.68 | ||
CC | 354 (62.7%) | 292 (62.7%) | ||||||
CT | 185 (32.7%) | 148 (31.8%) | ||||||
TT | 26 (4.6%) | 26 (5.6%) | ||||||
C | 893 (79%) | 732 (78.5%) | ||||||
T | 237 (21%) | 200 (21.5%) |
Association analyses of TF and TFPI polymorphisms with outcome of severe sepsis
Gene | Survivor | Nonsurvivor | Allelic comparison | Genotypic comparison | ||||
---|---|---|---|---|---|---|---|---|
SNP | P 1adj | OR 1adj (95% CI) | P 2adj | OR 2adj (95% CI) | P 1adj | P 2adj | ||
TF
| ||||||||
rs1324214 | 0.06 | 0.73 (0.53 to 1.01) | 0.12 | 0.78 (0.56 to 1.16) | 0.13 | 0.24 | ||
CC | 165 (55%) | 103 (62.8%) | ||||||
CT | 118 (39.3%) | 57 (34.8%) | ||||||
TT | 17 (5.7%) | 4 (2.4%) | ||||||
T | 448 (74.7%) | 263 (80.2%) | ||||||
C | 152 (25.3%) | 65 (19.8%) | ||||||
rs762484 | 0.13 | 0.75 (0.51 to 1.09) | 0.26 | 0.78 (0.82 to 1.07) | 0.32 | 0.38 | ||
TT | 208 (68.6%) | 124 (74.7%) | ||||||
TC | 85 (28%) | 39 (23.5%) | ||||||
CC | 10 (3.3%) | 3 (1.8%) | ||||||
T | 501 (82.7%) | 287 (86.4%) | ||||||
C | 105 (17.3%) | 45 (13.6%) | ||||||
rs696619 | 0.23 | 0.84 (0.63 to 1.12) | 0.38 | 0.86 (0.73 to 1.09) | 0.41 | 0.52 | ||
AA | 122 (40.4%) | 75 (45.7%) | ||||||
AG | 156 (51.7%) | 80 (48.8%) | ||||||
GG | 24 (7.9%) | 9 (5.5%) | ||||||
A | 400 (66.2%) | 230 (70.1%) | ||||||
G | 204 (33.8%) | 98 (29.9%) | ||||||
rs3917615 | 0.00015 | 0.50 (0.35 to 0.72) | 0.0018 | 0.69 (0.45 to 0.82) | 0.00014 | 0.0017 | ||
CC | 167 (55.1%) | 123 (74.5%) | ||||||
CT | 126 (41.6%) | 39 (23.6%) | ||||||
TT | 10 (3.3%) | 3 (1.8%) | ||||||
C | 460 (75.9%) | 285 (86.4%) | ||||||
T | 146 (24.1%) | 445 (13.6%) | ||||||
rs1361600 | 0.000049 | 0.48 (0.33 to 0.69) | 0.00045 | 0.57 (0.41 to 0.74) | 0.000024 | 0.00065 | ||
AA | 164 (53.6%) | 124 (74.7%) | ||||||
AG | 130 (42.5%) | 38 (22.9%) | ||||||
GG | 12 (3.9%) | 4 (2.4%) | ||||||
A | 458 (74.8%) | 286 (86.1%) | ||||||
G | 154 (25.2%) | 46 (13.9%) | ||||||
rs958587 | 0.0001 | 0.50 (0.34 to 0.71) | 0.0015 | 0.67 (0.43 to 0.79) | 0.000094 | 0.0016 | ||
CC | 164 (53.9%) | 122 (73.9%) | ||||||
CT | 130 (42.8%) | 40 (24.2%) | ||||||
TT | 10 (3.3%) | 3 (1.8%) | ||||||
C | 458 (75.3%) | 284 (86%) | ||||||
T | 150 (24.7%) | 46 (14%) | ||||||
rs3917643 | 0.62 | 1.84 (0.26 to 13.10) | 0.78 | 1.48 (0.76 to 14.07) | 0.62 | 0.78 | ||
AA | 304 (99.3%) | 165 (98.8%) | ||||||
AG | 2 (0.7%) | 2 (1.2%) | ||||||
A | 610 (99.7%) | 332 (99.4%) | ||||||
G | 2 (0.3%) | 2 (0.6%) | ||||||
rs145977586 | 1.00 | 0.92 (0.08 to 10.14) | 0.95 | 0.93 (0.12 to 12.76) | 1.00 | 0.95 | ||
GG | 304 (99.3%) | 166 (99.4%) | ||||||
GA | 2 (0.7%) | 1 (0.6%) | ||||||
G | 610 (99.7%) | 333 (99.7%) | ||||||
A | 2 (0.3%) | 1 (0.3%) | ||||||
TFPI
| ||||||||
rs3755248 | 0.75 | 0.94 (0.63 to 1.39) | 0.62 | 0.84 (0.56 to 1.23) | 0.13 | 0.11 | ||
TT | 222 (72.8%) | 126 (76.4%) | ||||||
TC | 80 (26.2%) | 34 (20.6%) | ||||||
CC | 3 (1%) | 5 (3%) | ||||||
T | 524 (85.9%) | 286 (86.7%) | ||||||
C | 86 (14.1%) | 44 (13.3%) | ||||||
rs3213739 | 0.16 | 0.82 (0.62 to 1.08) | 0.25 | 0.85 (0.72 to 1.04) | 0.44 | 0.52 | ||
GG | 135 (44.7%) | 84 (50.9%) | ||||||
GT | 84 (27.8%) | 41 (24.8%) | ||||||
TT | 83 (27.5%) | 40 (24.2%) | ||||||
G | 354 (58.6%) | 209 (63.3%) | ||||||
T | 250 (41.4%) | 121 (36.7%) | ||||||
rs7594359 | 0.18 | 0.78 (0.54 to 1.12) | 0.12 | 0.71 (0.46 to 1.09) | 0.23 | 0.18 | ||
CC | 197 (64.8%) | 120 (71.9%) | ||||||
CT | 104 (34.2%) | 45 (26.9%) | ||||||
TT | 3 (1%) | 2 (1.2%) | ||||||
C | 498 (81.9%) | 285 (85.3%) | ||||||
T | 110 (18.1%) | 49 (14.7%) | ||||||
rs10931292 | 0.44 | 0.89 (0.67 to 1.19) | 0.47 | 0.91 (0.81 to 1.13) | 0.38 | 0.49 | ||
TT | 142 (47%) | 87 (52.7%) | ||||||
TC | 122 (40.4%) | 56 (33.9%) | ||||||
CC | 38 (12.6%) | 22 (13.3%) | ||||||
T | 406 (67.2%) | 230 (69.7%) | ||||||
C | 198 (32.8%) | 100 (30.3%) | ||||||
rs8176441 | 0.87 | 1.03 (0.75 to 1.40) | 0.95 | 0.92 (0.61 to 1.32) | 0.06 | 0.17 | ||
TT | 185 (60.9%) | 90 (55.6%) | ||||||
TC | 89 (29.3%) | 63 (38.9%) | ||||||
CC | 30 (9.8%) | 9 (5.5%) | ||||||
T | 459 (75.5%) | 243 (75%) | ||||||
C | 149 (24.5%) | 81 (25%) | ||||||
rs12613071 | 0.91 | 1.02 (0.76 to 1.37) | 0.72 | 1.12 (0.83 to 1.58) | 0.32 | 0.21 | ||
TT | 150 (50.2%) | 86 (52.8%) | ||||||
TC | 124 (41.5%) | 58 (35.6%) | ||||||
CC | 25 (8.4%) | 19 (11.7%) | ||||||
T | 424 (70.9%) | 230 (70.6%) | ||||||
C | 174 (29.1%) | 96 (29.4%) | ||||||
rs10153820 | 0.20 | 1.21 (0.91 to 1.61) | 0.45 | 1.15 (0.82 to 1.46) | 0.25 | 0.52 | ||
CC | 161 (53.5%) | 76 (45.8%) | ||||||
CT | 105 (34.9%) | 70 (42.2%) | ||||||
TT | 35 (11.6%) | 20 (12%) | ||||||
C | 427 (70.9%) | 222 (66.9%) | ||||||
T | 175 (29.1%) | 110 (33.1%) | ||||||
rs8176592 | 0.35 | 0.81 (0.52 to 1.26) | 0.62 | 0.84 (0.71 to 1.19) | 0.34 | 0.58 | ||
TT | 234 (77%) | 133 (81.6%) | ||||||
TC | 68 (22.4%) | 28 (17.2%) | ||||||
CC | 2 (0.6%) | 2 (1.2%) | ||||||
T | 536 (88.2%) | 294 (90.2%) | ||||||
C | 72 (11.8%) | 32 (9.8%) | ||||||
rs2192824 | 0.48 | 0.89 (0.64 to 1.24) | 0.52 | 0.91 (0.72 to 1.19) | 0.38 | 0.41 | ||
CC | 190 (62.9%) | 106 (63.9%) | ||||||
CT | 94 (31.1%) | 55 (33.1%) | ||||||
TT | 18 (6%) | 5 (3%) | ||||||
C | 474 (78.5%) | 267 (80.4%) | ||||||
T | 130 (21.5%) | 65 (19.6%) |
Association analyses of tissue factor mRNA expression levels with rs1361600 genotypes
Association analyses of tissue factor plasma levels with rs1361600 genotypes
Discussion
Conclusion
Key messages
-
Individuals carrying the G allele of rs1361600 in the TF gene have a lower risk for death of severe sepsis in Chinese Han population.
-
SNP rs1361600 influences the expression of TF mRNA and the protein production of TF in patients with severe sepsis.