Introduction
Materials and methods
Patients and samples
HLA-A and HLA-B*51genotyping
Statistical analysis
Results
Clinical characteristics of BD patients
Gender (M:F) | 110:113 |
Age at diagnosis (years, mean ± SD) | 43.1 ± 10.0 |
Disease duration (years, mean ± SD) | 12.8 ± 9.2 |
Clinical manifestations | n (%) |
Oral ulcer | 223 (100) |
Genital ulcer | 159 (71.3) |
Skin lesions | 180 (80.7) |
Positive pathergy test | 94/182 (51.6) |
Uveitis | 85 (38.1) |
Retinal vasculitis | 10 (4.5) |
Joint involvement | 125 (56.1) |
Vascular involvement | 33 (14.8) |
Central nervous system involvement | 10 (4.5) |
HLA-B*51† | 81 (36.3) |
Phenotypic frequencies of the HLA-Aalleles
All subjects | OR (95% CI) | P
(Pc) | HLA-B*51non-carriers | OR (95% CI) | P
(Pc) | HLA-B*51carriers | OR (95% CI) | P
(Pc) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BD N= 223 | Control N= 1,398 | BD N= 142 | Control N= 1,116 | BD N= 81 | Control N= 282 | |||||||||||||
A*01:01
| 2 | (0.9) | 45 | (3.2) | 0.27 (0.07 to 1.13) | 2 | (1.4) | 38 | (3.4) | 0.41 (0.10 to 1.70) | 0 | (0.0) | 7 | (2.5) | NA | |||
A*02:01
| 77 | (34.5) | 433 | (31.0) | 1.18 (0.87 to 1.58) | 46 | (32.4) | 359 | (32.2) | 1.01 (0.70 to 1.47) | 31 | (38.3) | 74 | (26.2) | 1.74 (1.04 to 2.93) | 0.035 (> 1.0) | ||
A*02:03
| 4 | (1.8) | 19 | (1.4) | 1.33 (0.45 to 3.93) | 3 | (2.1) | 19 | (1.7) | 1.25 (0.36 to 4.26) | 1 | (1.2) | 0 | (0.0) | NA | |||
A*02:05
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | |||
A*02:06
| 35 | (15.7) | 250 | (17.9) | 0.85 (0.58 to 1.26) | 18 | (12.7) | 193 | (17.3) | 0.69 (0.41 to 1.17) | 17 | (21.0) | 57 | (20.2) | 1.05 (0.57 to 1.93) | |||
A*02:07
| 27 | (12.1) | 89 | (6.4) | 2.03 (1.28 to 3.20) | 0.002 (0.06) | 19 | (13.4) | 80 | (7.2) | 2.00 (1.17 to 3.41) | 0.010 (> 1.0) | 8 | (9.9) | 9 | (3.2) | 3.32 (1.24 to 8.92) | 0.031 (> 1.0) |
A*02:10
| 0 | (0.0) | 13 | (0.9) | NA | 0 | (0.0) | 12 | (1.1) | NA | 0 | (0.0) | 1 | (0.4) | NA | |||
A*03:01
| 3 | (1.4) | 35 | (2.5) | 0.53 (0.16 to 1.74) | 3 | (2.1) | 28 | (2.5) | 0.84 (0.25 to 2.79) | 0 | (0.0) | 7 | (2.5) | NA | |||
A*03:02
| 1 | (0.5) | 6 | (0.4) | 1.05 (0.13 to 8.72) | 1 | (0.7) | 5 | (0.5) | 1.58 (0.18 to 13.59) | 0 | (0.0) | 1 | (0.4) | NA | |||
A*11:01
| 39 | (17.5) | 242 | (17.3) | 1.01 (0.70 to 1.47) | 25 | (17.6) | 188 | (16.9) | 1.05 (0.67 to 1.67) | 14 | (17.3) | 54 | (19.2) | 0.88 (0.46 to 1.69) | |||
A*11:02
| 2 | (0.9) | 2 | (0.1) | 6.32 (0.89 to 45.08) | 1 | (0.7) | 1 | (0.1) | 7.91 (0.49 to 127 to 13) | 1 | (1.2) | 1 | (0.4) | 3.5 (0.22 to 56.58) | |||
A*24:02
| 95 | (42.6) | 578 | (41.3) | 1.05 (0.79 to 1.40) | 54 | (38.0) | 442 | (39.6) | 0.94 (0.65 to 1.34) | 41 | (50.6) | 136 | (48.2) | 1.10 (0.67 to 1.80) | |||
A*24:03
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | |||
A*24:04
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | |||
A*24:08
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | |||
A*24:20
| 1 | (0.5) | 2 | (0.1) | 3.14 (0.28 to 34.82) | 1 | (0.7) | 2 | (0.2) | 3.95 (0.36 to 43.84) | 0 | (0.0) | 0 | (0.0) | NA | |||
A*26:01
| 26 | (11.7) | 93 | (6.7) | 1.85 (1.17 to 2.93) | 0.008 (0.24) | 19 | (13.4) | 74 | (6.6) | 2.18 (1.27 to 3.72) | 0.004 (0.12) | 7 | (8.6) | 19 | (6.7) | 1.31 (0.53 to 3.23) | |
A*26:02
| 11 | (4.9) | 58 | (4.2) | 1.20 (0.62 to 2.32) | 7 | (4.9) | 46 | (4.1) | 1.21 (0.53 to 2.73) | 4 | (4.9) | 12 | (4.3) | 1.17 (0.37 to 3.72) | |||
A*26:03
| 7 | (3.1) | 17 | (1.2) | 2.63 (1.08 to 6.42) | 0.037 (> 1.0) | 5 | (3.5) | 14 | (1.3) | 2.87 (1.02 to 8.10) | 0.053 | 2 | (2.5) | 3 | (1.1) | 2.35 (0.39 to 14.34) | |
A*26:05
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | 0 | (0.0) | 1 | (0.4) | NA | |||
A*26:18
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | |||
A*29:01
| 2 | (0.9) | 28 | (2.0) | 0.44 (0.10 to 1.87) | 2 | (1.4) | 24 | (2.2) | 0.65 (0.15 to 2.78) | 0 | (0.0) | 4 | (1.4) | NA | |||
A*29:02
| 1 | (0.5) | 0 | (0.0) | NA | 1 | (0.7) | 0 | (0.0) | NA | 0 | (0.0) | 0 | (0.0) | NA | |||
A*30:01
| 8 | (3.6) | 74 | (5.3) | 0.67 (0.32 to 1.40) | 7 | (4.9) | 63 | (5.7) | 0.87 (0.39 to 1.93) | 1 | (1.2) | 11 | (3.9) | 0.31 (0.04 to 2.42) | |||
A*30:04
| 12 | (5.4) | 31 | (2.2) | 2.51 (1.27 to 4.96) | 0.006 (0.18) | 11 | (7.8) | 26 | (2.3) | 3.52 (1.70 to 7.29) | 0.002 (0.06) | 1 | (1.2) | 5 | (1.8) | 0.69 (0.08 to 6.01) | |
A*31:01
| 22 | (9.9) | 160 | (11.4) | 0.85 (0.53 to 1.35) | 10 | (7.0) | 98 | (8.8) | 0.79 (0.40 to 1.55) | 12 | (14.8) | 62 | (22.0) | 0.62 (0.31 to 1.21) | |||
A*31:11
| 0 | (0.0) | 1 | (0.1) | NA | 0 | (0.0) | 0 | (0.0) | NA | 0 | (0.0) | 1 | (0.4) | NA | |||
A*32:01
| 0 | (0.0) | 26 | (1.9) | NA | 0 | (0.0) | 25 | (2.2) | NA | 0 | (0.0) | 1 | (0.4) | NA | |||
A*33:03
| 43 | (19.3) | 405 | (29.0) | 0.59 (0.41 to 0.83) | 0.003 (0.09) | 33 | (23.2)† | 345 | (30.9) | 0.68 (0.45 to 1.02) | 10 | (12.4) | 60 | (21.3) | 0.52 (0.25 to 1.07) | ||
A*68:01
| 1 | (0.5) | 3 | (0.2) | 2.09 (0.22 to 20.23) | 1 | (0.7) | 2 | (0.2) | 3.95 (0.36 to 43.85) | 0 | (0.0) | 1 | (0.4) | NA |
Meta-analysis of the case-control genetic association studies between HLA-Agenes and BD susceptibility
Allele | Total subjects | HLA-B*51 non-carriers | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
OR (95% CI) | P
| I2 (%) | P
het
| Weight (%) | OR (95% CI) | P
| I2 (%) | P
het
| Weight (%) | |
A*01:01
| 0.54 (0.21 to 1.42) | 0.21 | 76 | 0.04 | 92.7 | 0.65 (0.22 to 1.91) | 0.43 | 60 | 0.11 | 92.7 |
A*02:01
| 1.20 (0.97 to 1.48) | 0.09 | 0 | 0.70 | 65.7 | 1.13 (0.87 to 1.47) | 0.37 | 0 | 0.33 | 70.5 |
A*02:03
| 0.96 (0.35 to 2.65) | 0.93 | 27 | 0.24 | 67.5 | 0.99 (0.32 to 3.09) | 0.99 | 0 | 0.47 | 70.9 |
A*02:06
| 0.86 (0.66 to 1.13) | 0.28 | 0 | 0.69 | 58.2 | 0.73 (0.50 to 1.06) | 0.10 | 0 | 0.62 | 60.7 |
A*02:07
| 1.96 (1.34 to 2.85) | 0.0005 | 0 | 0.62 | 66.6 | 2.00 (1.30 to 3.09) | 0.002 | 0 | 0.69 | 69.7 |
A*02:10
| 0.37 (0.06 to 2.37) | 0.30 | 0 | 0.43 | 80.0 | 0.37 (0.05 to 3.05) | 0.36 | 0 | 0.72 | 74.5 |
A*03:01
| 0.44 (0.15 to 1.26) | 0.13 | 0 | 0.56 | 71.1 | 0.77 (0.26 to 2.21) | 0.62 | 0 | 0.84 | 75.7 |
A*03:02
| 0.71 (0.12 to 4.21) | 0.70 | 0 | 0.56 | 52.4 | 1.12 (0.18 to 6.77) | 0.90 | 0 | 0.64 | 51.9 |
A*11:01
| 0.78 (0.60 to 1.03) | 0.08 | 77 | 0.04 | 50.5 | 0.85 (0.61 to 1.19) | 0.35 | 51 | 0.15 | 50.6 |
A*11:02
| 1.30 (0.30 to 5.57) | 0.73 | 75 | 0.05 | 18.0 | 1.23 (0.20 to 7.71) | 0.82 | 57 | 0.13 | 11.5 |
A*24:02
| 0.89 (0.75 to 1.05) | 0.18 | 44 | 0.18 | 47.0 | 0.83 (0.67 to 1.03) | 0.10 | 0 | 0.43 | 48.8 |
A*24:20
| 0.60 (0.13 to 2.83) | 0.52 | 59 | 0.12 | 12.1 | 0.68 (0.12 to 3.73) | 0.65 | 63 | 0.10 | 12.6 |
A*26:01
| 1.89 (1.41 to 2.53) | <0.0001 | 0 | 0.91 | 38.9 | 2.42 (1.73 to 3.39) | <0.00001 | 0 | 0.62 | 41.3 |
A*26:02
| 1.48 (0.90 to 2.42) | 0.12 | 7 | 0.30 | 64.5 | 1.93 (1.09 to 3.40) | 0.02 | 69 | 0.07 | 69.1 |
A*26:03
| 2.01 (1.14 to 3.56) | 0.02 | 0 | 0.51 | 28.4 | 2.40 (1.17 to 4.91) | 0.02 | 0 | 0.70 | 36.6 |
A*26:05
| 3.69 (0.44 to 31.24) | 0.23 | 0 | 0.69 | 45.3 | NA | ||||
A*31:01
| 1.22 (0.91 to 1.62) | 0.18 | 79 | 0.03 | 51.9 | 0.73 (0.45 to 1.19) | 0.21 | 0 | 0.76 | 51.8 |
A*33:03
| 0.52 (0.39 to 0.70) | <0.00001 | 64 | 0.09 | 71.0 | 0.58 (0.41 to 0.81) | 0.001 | 67 | 0.08 | 71.3 |
Associations between HLA-Aalleles and clinical features of BD
HLA alleles | Group | Phenotypic frequency n(%) | OR (95% CI) | P
| Pc
|
---|---|---|---|---|---|
All subjects | |||||
A*02:07
| Patients with skin lesions (n = 180) | 25 (13.9) | |||
vs. Patients without skin lesions (n = 43) | 2 (4.7) | 3.31 (0.75 to 14.54) | 0.095 | ||
vs. Controls (n = 1,398) | 89 (6.4) | 2.37 (1.48 to 3.31) | <0.0005 | <0.012 | |
Patients with arthritis (n = 125) | 17 (13.6) | ||||
vs. Patients without arthritis (n = 98) | 10 (10.2) | 1.39 (0.60 to 3.18) | 0.438 | ||
vs. Controls (n = 1,398) | 89 (6.4) | 2.32 (1.33 to 4.03) | 0.002 | 0.048 | |
A*26:01
| Patients with uveitis (n = 85) | 15 (17.7) | |||
vs. Patients without uveitis (n = 138) | 11 (8.0) | 2.47 (1.08 to 5.68) | 0.029 | ||
vs. Controls (n = 1,398) | 93 (6.7) | 3.01 (1.66 to 5.46) | <0.0005 | <0.012 | |
A*30:04
| Patients with vascular lesions (n = 33) | 6 (18.2) | |||
vs. Patients without vascular lesions (n = 190) | 6 (3.2) | 6.81 (2.05 to 22.66) | 0.003 | ||
vs. Controls (n = 1,398) | 31 (2.2) | 9.80 (3.78 to 25.43) | <0.0005 | <0.012 | |
Patients with genital ulcers (n = 159) | 10 (6.3) | ||||
vs. Patients without genital ulcers (n = 64) | 2 (3.1) | 2.08 (0.44 to 9.77) | 0.516 | ||
vs. Controls (n = 1,398) | 31 (2.2) | 3.00 (1.42 to 6.16) | 0.006 | 0.14 | |
Patients with positive pathergy test (n = 94) | 8 (8.5) | ||||
vs. Patients with negative pathergy test (n = 88) | 3 (3.4) | 2.19 (0.74 to 6.46) | 0.147 | ||
vs. Controls (n = 1,398) | 31 (2.2) | 4.10 (1.83 to 9.20) | 0.002 | 0.048 | |
HLA-B*51 non-carriers | |||||
A*02:07
| Patients with skin lesions (n = 109) | 17 (15.6) | |||
vs. Patients without skin lesions (n = 33) | 2 (6.1) | 2.86 (0.63 to 13.10) | 0.243 | ||
vs. Controls (n = 1,116) | 80 (7.2) | 2.39 (1.36 to 4.21) | 0.002 | 0.048 | |
Patients with arthritis (n = 83) | 14 (16.9) | ||||
vs. Patients without arthritis (n = 59) | 5 (8.5) | 2.19 (0.74 to 6.46) | 0.147 | ||
vs. Controls (n = 1,116) | 80 (7.2) | 2.63 (1.42 to 4.87) | 0.002 | 0.048 | |
A*26:01
| Patients with uveitis (n = 48) | 11 (22.9) | |||
vs. Patients without uveitis (n = 94) | 8 (8.5) | 3.20 (1.19 to 8.59) | 0.017 | ||
vs. Controls (n = 1,116) | 74 (6.6) | 4.19 (2.05 to 8.54) | <0.0005 | <0.012 | |
A*30:04
| Patients with vascular lesions (n = 24) | 6 (25.0) | |||
vs. Patients without vascular lesions (n = 118) | 5 (4.2) | 7.53 (2.08 to 27.28) | 0.003 | ||
vs. Controls (n = 1,116) | 26 (2.3) | 13.97 (5.13 to 38.08) | <0.00005 | <0.0012 | |
Patients with genital ulcers (n = 106) | 9 (8.5) | ||||
vs. Patients without genital ulcers (n = 36) | 2 (5.6) | 1.58 (0.32 to 7.67) | 0.730 | ||
vs. Controls (n = 1,116) | 26 (2.3) | 3.89 (1.77 to 8.54) | 0.002 | 0.048 | |
Patients with positive pathergy test (n = 57) | 7 (12.3) | ||||
vs. Patients with negative pathergy test (n = 58) | 3 (5.2) | 2.57 (0.63 to 10.47) | 0.203 | ||
vs. Controls (n = 1,116) | 26 (2.3) | 5.87 (2.43 to 14.17) | 0.001 | 0.024 |
Associations between HLA-A alleles and clinical features of BD in HLA-B*51non-carriers
Distribution of clinical manifestations according to HLA-B*51 and HLA-Astatus
Patient subset | n(%) of clinical manifestations | OR (95% CI) | P
|
---|---|---|---|
Skin lesions | |||
B*51+ A*02:07+
| 8/8 (100) | NA | 0.20 |
B*51- A*02:07+
| 17/19 (89.5) | 2.86 (0.63 to 13.10) | 0.24 |
B*51+ A*02:07-
| 63/73 (86.3) | 2.12 (0.97 to 4.64) | 0.055 |
B*51- A*02:07-
| 92/123 (74.8) | (referent) | |
Uveitis | |||
B*51+ A*26:01+
| 4/7 (57.1) | 3.10 (0.66 to 14.53) | 0.21 |
B*51- A*26:01+
| 11/19 (57.9) | 3.20 (1.19 to 8.59) | 0.017 |
B*51+ A*26:01-
| 33/74 ((44.6) | 1.87 (1.03 to 3.40) | 0.039 |
B*51- A*26:01-
| 37/123 (30.1) | (referent) |