Introduction
Methods
Patients and controls
Genotyping methods
Assay for serum levels of IL-33
Statistical analyses
Results
Population characteristics
Discovery population | Validation population | Replication population | |
---|---|---|---|
Number of cases | 700 | 586 | 666 |
Ethnicity | Northern Han Chinese | Southern Han Chinese | Northern and Southern |
Female, % | 79.9 | 81.2 | 82.8 |
Age, mean ± SD years | 54.0 ± 13.1 | 52.4 ± 13.9 | 54.3 ± 12.8 |
Age at RA onset, mean ± SD years | 46.4 ± 16.0 | 46.3 ± 15.0 | 46.6 ± 15.4 |
Disease duration, mean ± SD years | 8.1 ± 8.1 | 7.8 ± 7.3 | 9.0 ± 10.3 |
ACPA status, % positive | 72.6 | 75.3 | 68.9 |
RF status, % positive | 81.6 | 78.3 | 84.0 |
Association analysis of rs7044343 with RA
Characteristic ( n) | Allele frequency (%) | Genotype frequency (%) | T versus C | CC versus TT + TC | CC + TC versus TT | |||
---|---|---|---|---|---|---|---|---|
T | C | TT | TC | CC | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
P value | P value | P value | ||||||
Control (598) | 545 (45.6) | 651 (54.4) | 137 (22.9) | 271 (45.3) | 190 (31.8) | |||
RA (700) | 641 (45.8) | 759 (54.2) | 127 (18.1) | 387 (55.3) | 186 (26.6) | 1.009 | 0.777 | 1.354 |
(0.864-1.178) | (0.611-0.988) | (1.033-1.774) | ||||||
0.912 | 0.040* | 0.028* | ||||||
RF + (418) | 377 (45.1) | 459 (54.9) | 78 (18.7) | 221 (52.9) | 119 (28.5) | 0.981 | 0.855 | 1.308 |
(0.822-1.172) | (0.650-1.123) | (0.958-1.785) | ||||||
0.833 | 0.260 | 0.091 | ||||||
RF- (94) | 86 (45.7) | 102 (54.3) | 17 (18.1) | 52 (55.3) | 25 (26.6) | 1.007 | 0.778 | 1.359 |
(0.740-1.371) | (0.477-1.269) | (0.777-2.376) | ||||||
0.964 | 0.314 | 0.282 | ||||||
ACP (300) | 281 (46.8) | 319 (53.2) | 62 (20.7) | 157 (52.3) | 81 (27.0) | 1.052 | 0.794 | 1.152 |
(0.864-1.281) | (0.584-1.080) | (0.821-1.615) | ||||||
0.612 | 0.142 | 0.413 | ||||||
ACPA - (113) | 108 (47.8) | 118 (52.2) | 20 (17.7) | 68 (60.2) | 25 (22.1) | 1.093 | 0.610 | 1.395 |
(0.822-1.453) | (0.379-0.982) | (0.830-2.345) | ||||||
0.539 | 0.042* | 0.209 | ||||||
Female control (465) | 432 (46.5) | 498 (53.5) | 106 (22.8) | 220 (47.3) | 139 (29.9) | |||
Female RA (482) | 426 (44.2) | 538 (55.8) | 85 (17.6) | 256 (53.1) | 141 (29.3) | 0.913 | 0.970 | 1.396 |
(0.762-1.094) | (0.734-1.282) | (1.015-1.920) | ||||||
0.323 | 0.829 | 0.040 | ||||||
Female RF+ (333) | 300 (45.0) | 366 (55.0) | 62 (18.6) | 176 (52.9) | 95 (28.5) | 0.945 | 0.936 | 1.306 |
(0.774-1.154) | (0.687-1.276) | (0.920-1.855) | ||||||
0.578 | 0.676 | 0.135 | ||||||
Female RF- (75) | 64 (42.7) | 86 (57.3) | 12 (16.0) | 40 (53.3) | 23 (30.7) | 0.858 | 1.037 | 1.569 |
(0.606-1.215) | (0.611-1.761) | (0.816-3.018) | ||||||
0.388 | 0.892 | 0.177 | ||||||
Female ACPA+ (243) | 225 (46.3) | 261 (53.7) | 50 (20.6) | 125 (51.4) | 68 (28.0) | 0.994 | 0.911 | 1.154 |
(0.798-1.238) | (0.647-1.285) | (0.790-1.685) | ||||||
0.956 | 0.596 | 0.459 | ||||||
Female ACPA- (84) | 77 (45.8) | 91 (54.2) | 15 (17.9) | 47 (56.0) | 22 (26.2) | 0.975 | 0.832 | 1.375 |
(0.701-1.356) | (0.492-1.407) | (0.756-2.502) | ||||||
0.882 | 0.493 | 0.297 | ||||||
Male CON (105) | 99 (47.1) | 111 (52.9) | 26 (24.8) | 47 (44.8) | 32 (30.5) | |||
Male RA (121) | 116 (47.9) | 126 (52.1) | 24 (19.8) | 68 (56.2) | 29 (24.0) | 1.032 | 0.719 | 1.330 |
(0.713-1.495) | (0.399-1.296) | (0.709-2.496) | ||||||
0.867 | 0.272 | 0.374 | ||||||
Male RF+ (84) | 75 (44.6) | 93 (55.4) | 15 (17.9) | 45 (53.6) | 24 (28.6) | 0.904 | 0.913 | 1.514 |
(0.602-1.359) | (0.486-1.713) | (0.742-3.088) | ||||||
0.628 | 0.776 | 0.254 | ||||||
Male RF- (19) | 22 (57.9) | 16 (42.1) | 5 (26.3) | 12 (63.2) | 2 (10.5) | 1.542 | 0.268 | 0.922 |
(0.767-3.100) | (0.059-1.231) | (0.303-2.805) | ||||||
0.222 | 0.090 | 0.886 | ||||||
Male ACPA+ (57) | 56 (49.1) | 58 (50.9) | 12 (21.1) | 32 (56.1) | 13 (22.8) | 1.083 | 0.674 | 1.234 |
(0.686-1.709) | (0.320-1.420) | (0.568-2.681) | ||||||
0.733 | 0.300 | 0.595 | ||||||
Male ACPA- (27) | 29 (53.7) | 25 (46.3) | 5 (18.5) | 19 (70.4) | 3 (11.1) | 1.301 | 0.285 | 1.448 |
(0.714-2.369) | (0.080-1.016) | (0.498-4.211) | ||||||
0.390 | 0.053 | 0.497 |
Characteristic ( n) | Allele frequency (%) | Genotype frequency (%) | T vs. C | CC vs. TT + TC | CC + TC vs. TT | |||
---|---|---|---|---|---|---|---|---|
T | C | TT | TC | CC | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
P value | P value | P value | ||||||
Control (456) | 409 (44.8) | 503 (55.2) | 100 (21.9) | 209 (45.8) | 147 (32.2) | |||
RA (586) | 548 (46.8) | 624 (53.2) | 118 (20.1) | 312 (53.2) | 156 (26.6) | 1.080 | 0.763 | 1.114 |
(0.908-1.285) | (0.583-0.998) | (0.825-1.504) | ||||||
0.385 | 0.048* | 0.480 | ||||||
RF + (354) | 322 (45.5) | 386 (54.5) | 67 (18.9) | 188 (53.1) | 99 (28.0) | 1.026 | 0.816 | 1.203 |
(0.842-1.250) | (0.602-1.106) | (0.851-1.701) | ||||||
0.799 | 0.190 | 0.295 | ||||||
RF- (98) | 100 (51.0) | 96 (49.0) | 25 (25.5) | 50 (51.0) | 23 (23.5) | 1.281 | 0.645 | 0.820 |
(0.941-1.745) | (0.388-1.070) | (0.495-1.360) | ||||||
0.116 | 0.089 | 0.442 | ||||||
ACPA + (281) | 257 (45.7) | 305 (54.3) | 51 (18.1) | 155 (55.2) | 75 (26.7) | 1.036 | 0.765 | 1.267 |
(0.839-1.280) | (0.551-1.064) | (0.870-1.845) | ||||||
0.741 | 0.111 | 0.217 | ||||||
ACPA- (92) | 94 (51.1) | 90 (48.9) | 21 (22.8) | 52 (56.5) | 19 (20.7) | 1.284 | 0.547 | 0.950 |
(0.935-1.764) | (0.318-0.940) | (0.556-1.622) | ||||||
0.121 | 0.029* | 0.850 | ||||||
Female control (363) | 319 (43.9) | 407 (56.1) | 75 (20.7) | 169 (46.6) | 119 (32.8) | |||
Female RA (441) | 413 (46.8) | 469 (53.2) | 87 (19.7) | 239 (54.2) | 115 (26.1) | 1.124 | 0.723 | 1.060 |
(0.922-1.369) | (0.533-0.982) | (0.750-1.497) | ||||||
0.247 | 0.038 | 0.743 | ||||||
Female RF+ (291) | 264 (45.4) | 318 (54.6) | 53 (18.2) | 158 (54.3) | 80 (27.5) | 1.059 | 0.777 | 1.169 |
(0.851-1.319) | (0.554-1.090) | (0.791-2.730) | ||||||
0.607 | 0.144 | 0.433 | ||||||
Female RF- (75) | 77 (51.3) | 73 (48.7) | 20 (26.7) | 37 (49.3) | 18 (24.0) | 1.346 | 0.648 | 0.716 |
(0.946-1.914) | (0.365-1.149) | (0.404-1.268) | ||||||
0.098 | 0.137 | 0.252 | ||||||
Female ACPA+ (234) | 217 (46.4) | 251 (53.6) | 43 (18.4) | 131 (56.0) | 60 (25.6) | 1.103 | 0.707 | 1.157 |
(0.873-1.393) | (0.490-1.020) | (0.762-1.755) | ||||||
0.410 | 0.064 | 0.494 | ||||||
Female ACPA- (73) | 74 (50.7) | 72 (49.3) | 18 (24.7) | 38 (52.1) | 17 (23.3) | 1.311 | 0.622 | 0.796 |
(0.919-1.872) | (0.347-1.118) | (0.441-1.435) | ||||||
0.135 | 0.112 | 0.448 | ||||||
Male CON (89) | 86 (48.3) | 92 (51.7) | 24 (27.0) | 38 (42.7) | 27 (30.3) | |||
Male RA (102) | 98 (48.0) | 106 (52.0) | 23 (22.5) | 52 (51.0) | 27 (26.5) | 0.956 | 0.827 | 1.268 |
(0.615-1.486) | (0.440-1.553) | (0.656-2. 452) | ||||||
0.840 | 0.554 | 0.480 | ||||||
Male RF+ (63) | 58 (46.0) | 68 (54.0) | 14 (22.2) | 30 (47.6) | 19 (30.2) | 0.827 | 0.992 | 1.292 |
(0.527-1.299) | (0.491-2.002) | (0.607-2.753) | ||||||
0.410 | 0.981 | 0.506 | ||||||
Male RF- (22) | 23 (52.3) | 21 (47.7) | 5 (22.7) | 13 (59.1) | 4 (18.2) | 1.172 | 0.510 | 1.255 |
(0.605-2.268) | (0.158-1.651) | (0.417-3.777) | ||||||
0.638 | 0.261 | 0.686 | ||||||
Male ACPA+ (47) | 40 (42.6) | 54 (57.4) | 8 (17.0) | 24 (51.1) | 15 (31.9) | 0.792 | 1.076 | 1.800 |
(0.479-1.311) | (0.502-2.306) | (0.737-4.397) | ||||||
0.365 | 0.850 | 0.197 | ||||||
Male ACPA- (18) | 19 (52.8) | 17 (47.2) | 3 (16.7) | 13 (72.2) | 2 (11.1) | 0.376 | 0.287 | 1.846 |
(0.207-0.686) | (0.062-1.336) | (0.491-6.946) | ||||||
0.001 | 0.112 | 0.364 |
Characteristic ( n) | Allele frequency (%) | Genotype frequency (%) | T vs. C | CC vs. TT + TC | CC + TC vs. TT | |||
---|---|---|---|---|---|---|---|---|
T | C | TT | TC | CC | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
P-value | P.-value | P-value | ||||||
Control (701) | 631 (45.0) | 771 (55.0) | 154 (22.0) | 323 (46.1) | 224 (32.0) | |||
RA (666) | 632 (47.4) | 700 (52.6) | 144 (21.6) | 344 (51.7) | 178 (26.7) | 1.103 | 0.777 | 1.021 |
(0.949-1.282) | (0.615-0.981) | (0.789-1.320) | ||||||
0.201 | 0.034* | 0.877 | ||||||
RF + (325) | 300 (46.2) | 350 (53.8) | 73 (22.5) | 154 (47.4) | 98 (30.2) | 1.047 | 0.919 | 0.972 |
(0.869-1.262) | (0.691-1.223) | (0.709-1.333) | ||||||
0.627 | 0.563 | 0.860 | ||||||
RF-(62) | 54 (43.5) | 70 (56.5) | 10 (16.1) | 34 (54.8) | 18 (29.0) | 0.943 | 0.871 | 1.464 |
(0.651-1.365) | (0.492-1.542) | (0.727-2.948) | ||||||
0.754 | 0.636 | 0.286 | ||||||
ACPA + (224) | 192 (42.9) | 256 (57.1) | 39 (17.4) | 114 (50.9) | 71 (31.7) | 0.916 | 0.988 | 1.335 |
(0.739-1.136) | (0.715-1.365) | (0.905-1.970) | ||||||
0.425 | 0.943 | 0.2145 | ||||||
ACPA-(101) | 103 (51.0) | 99 (49.0) | 23 (22.8) | 57 (56.4) | 21 (20.8) | 1.271 | 0.559 | 0.955 |
(0.946-1.708) | (0.337-0.927) | (0.580-1.571) | ||||||
0.111 | 0.024* | 0.856 | ||||||
Female Control (519) | 474 (45.7) | 564 (54.3) | 114 (22.0) | 246 (47.4) | 159 (30.6) | |||
Female RA (458) | 410 (44.8) | 506 (55.2) | 92 (20.1) | 226 (49.3) | 140 (30.6) | 1.040 | 0.997 | 1.120 |
(0.869-1.246) | (0.759-1.309) | (0.822-1.525) | ||||||
0.668 | 0.982 | 0.473 | ||||||
Female RF+ (256) | 237 (46.3) | 275 (53.7) | 56 (21.9) | 125 (48.8) | 75 (29.3) | 1.025 | 0.938 | 1.005 |
(0.829-1.268) | (0.676-1.302) | (0.700-1.444) | ||||||
0.817 | 0.703 | 0.977 | ||||||
Female RF- (53) | 46 (43.4) | 60 (56.6) | 8 (15.1) | 30 (56.6) | 15 (28.3) | 0.912 | 0.894 | 1.583 |
(0.610-1.365) | (0.478-1.672) | (0.726-3.455) | ||||||
0.655 | 0.725 | 0.248 | ||||||
Female ACPA+ (158) | 133 (42.1) | 183 (57.9) | 27 (17.1) | 79 (50.0) | 52 (32.9) | 0.865 | 1.111 | 1.366 |
(0.670-1.115) | (0.759-1.625) | (0.859-2.171) | ||||||
0.263 | 0.589 | 0.187 | ||||||
Female ACPA- (76) | 72 (47.4) | 80 (52.6) | 14 (18.4) | 44 (57.9) | 18 (23.7) | 1.071 | 0.703 | 1.247 |
(0.761-1.506) | (0.401-1.231) | (0.673-2.308) | ||||||
0.694 | 0.217 | 0.483 | ||||||
Male CON (130) | 125 (48.1) | 135 (51.9) | 30 (23.1) | 65 (50.0) | 35 (26.9) | |||
Male RA (95) | 75 (39.5) | 115 (60.5) | 16 (16.8) | 43 (45.3) | 36 (37.9) | 0.704 | 1.656 | 1.481 |
(0.482-1.029) | (0.939-2.921) | (0.754-2. 908) | ||||||
0.070 | 0.081 | 0.254 | ||||||
Male RF+ (54) | 42 (38.9) | 66 (61.1) | 10 (18.5) | 22 (40.7) | 22 (40.7) | 0.687 | 1.866 | 1.320 |
(0.435-1.085) | (0.958-3.636) | (0.594-2.934) | ||||||
0.107 | 0.067 | 0.496 | ||||||
Male RF- (9) | 8 (44.4) | 10 (55.6) | 2 (22.2) | 4 (44.4) | 3 (33.3) | 0.864 | 1.357 | 1.050 |
(0.330-2.259) | (0.322-5.723) | (0.207-5.325) | ||||||
0.765 | 0.677 | 0.953 | ||||||
Male ACPA+ (44) | 29 (33.0) | 59 (67.0) | 4 (9.1) | 21 (47.7) | 19 (43.2) | 0.531 | 2.063 | 3.000 |
(0.320-0.881) | (1.013-4.202) | (0. 993–9.065) | ||||||
0.014 | 0.046 | 0.052 | ||||||
Male ACPA- (11) | 13 (59.1) | 9 (40.9) | 5 (45.5) | 3 (27.3) | 3 (27.3) | 1.560 | 1.018 | 0.360 |
(0.644-3.776) | (0.255-4.055) | (0.103-1.263) | ||||||
0.321 | 0.980 | 0.111 |