Introduction
Methods
Study subjects
Serological viral marker testing, clinical characteristics, HBV genotyping and mutation analysis
Selection of HLA-DR SNPs and genotyping
Statistical analyses
Results
Characteristics of study subjects
Characteristic | Healthy controls (n = 792) | CHB (n = 586) | LC (n = 536) | HCC (n = 1500) | P value |
---|---|---|---|---|---|
Male (%) | 488 (61.62) | 416 (70.99) | 391 (72.95) | 1257 (83.80) | 0.001a, < 0.001b,c |
Age, years (mean ± SD) | 55.57 ± 13.06 | 43.99 ± 14.65 | 50.46 ± 10.84 | 53.02 ± 11.30 | 0.001a, < 0.001b,c |
HBeAg (%) | |||||
Positive | ND | 259 (44.20) | 202 (37.69) | 450 (30.00) | < 0.001b |
Negative | ND | 327 (55.80) | 334 (62.31) | 1050 (70.00) | |
Genotype (%) | ND | ||||
B | ND | 103 (23.62) | 86 (19.91) | 185 (16.53) | 0.003b |
C | ND | 333 (76.38) | 346 (80.09) | 934 (83.47) | |
HBV DNA load, log10 IU/mL (mean ± SD) | ND | 3.68 ± 0.91 | 3.45 ± 0.60 | 3.10 ± 0.44 | < 0.001b |
ALT, U/L (mean ± SD) | 20.47 ± 17.95 | 222.87 ± 497.96 | 124.14 ± 195.77 | 76.09 ± 171.97 | < 0.001a,b,c |
AST, U/L (mean ± SD) | 21.89 ± 13.44 | 133.35 ± 206.01 | 115.02 ± 133.44 | 83.81 ± 184.01 | < 0.001a,b,c |
TBiL, μmol/L (mean ± SD) | 12.91 ± 4.07 | 23.10 ± 35.52 | 54.97 ± 82.78 | 51.45 ± 89.83 | < 0.001a,b,c |
DBiL, μmol/L (mean ± SD) | 4.64 ± 7.28 | 9.45 ± 14.07 | 27.68 ± 50.89 | 25.78 ± 54.94 | < 0.001a,b,c |
ALP, U/L (mean ± SD) | 69.75 ± 25.41 | 109.08 ± 41.88 | 131.57 ± 61.38 | 141.49 ± 103.98 | < 0.001a,c, 0.035b |
GGT, U/L (mean ± SD) | 27.32 ± 24.65 | 87.86 ± 106.36 | 89.49 ± 131.91 | 157.80 ± 184.02 | < 0.001a,b,c |
ALB, g/L (mean ± SD) | 44.25 ± 5.06 | 42.30 ± 4.75 | 34.28 ± 7.31 | 36.84 ± 7.19 | < 0.001a,b,c |
PLT, 109/L (mean ± SD) | 205.10 ± 41.22 | 152.78 ± 43.47 | 86.43 ± 24.59 | 100.34 ± 28.44 | < 0.001a,b,c |
Associations of HLA-DR genetic polymorphisms with HCC risk
SNPs | Genotype | Healthy controls (%) | CHB plus LC (%) | HCC (%) | HCC versus. Healthy controls | HCC versus. HBV-infected subjects without HCC | |||
---|---|---|---|---|---|---|---|---|---|
AORa (95% CI) | P value | AORb (95% CI) | P value | ||||||
rs3135363 | AA | 465 (58.71) | 712 (63.46) | 1006 (67.07) | Reference | Reference | |||
AG | 276 (34.85) | 331 (29.50) | 438 (29.20) | 0.74 (0.61–0.89) | 0.001 | 0.93 (0.79–1.11) | 0.434 | ||
GG | 51 (6.44) | 79 (7.04) | 56 (3.73) | 0.52 (0.35–0.77 | 0.001 | 0.51 (0.36–0.73) | 1.97 × 10− 4 | ||
AG + GG | 327 (41.29) | 410 (36.54) | 494 (32.93) | 0.70 (0.55–0.90) | 9.59 × 10− 5 | 0.85 (0.73–1.03) | 0.054 | ||
rs9268644 | CC | 484 (61.11) | 631 (56.24) | 998 (66.53) | Reference | Reference | |||
CA | 264 (33.33) | 365 (32.53) | 394 (26.27) | 0.72 (0.66–0.88) | 0.001 | 0.68 (0.57–0.81) | 1.32 × 10− 5 | ||
AA | 44 (5.56) | 126 (11.23) | 108 (7.20) | 1.19 (0.83–1.72) | 0.352 | 0.54 (0.41–0.71) | 1.26 × 10− 5 | ||
CA + AA | 308 (38.89) | 491 (43.76) | 502 (33.47) | 0.79 (0.66–0.95) | 0.010 | 0.64 (0.55–0.76) | 6.33 × 10− 8 | ||
rs35445101 | AA | 531 (67.05) | 770 (68.63) | 1152 (76.80) | Reference | Reference | |||
AG | 95 (11.99) | 130 (11.59) | 158 (10.53) | 0.78 (0.59–1.02) | 0.071 | 0.81 (0.63–1.04) | 0.102 | ||
GG | 166 (20.96) | 222 (19.79) | 190 (12.67) | 0.53 (0.42–0.67) | 7.38 × 10− 8 | 0.57 (0.46–0.71) | 3.18 × 10− 7 | ||
AG + GG | 261 (32.95) | 352 (31.37) | 348 (23.20) | 0.62 (0.51–0.75) | 7.64 × 10− 7 | 0.66 (0.56–0.79) | 3.06 × 10− 6 | ||
rs24755213 | AA | 268 (33.84) | 404 (36.01) | 609 (40.60) | Reference | Reference | |||
AG | 392 (49.49) | 508 (45.28) | 635 (42.33) | 0.74 (0.61–0.89) | 0.002 | 0.85 (0.72–1.02) | 0.073 | ||
GG | 132 (16.67) | 210 (18.71) | 256 (17.07) | 0.88 (0.68–1.14) | 0.323 | 0.83 (0.67–1.04) | 0.104 | ||
AG + GG | 524 (66.16) | 718 (63.99) | 891 (59.40) | 0.77 (0.64–0.93) | 0.005 | 0.85 (0.72–0.99) | 0.044 | ||
rs984778 | TT | 358 (45.20) | 603 (53.74) | 813 (54.20) | Reference | Reference | |||
TC | 344 (43.43) | 429 (38.24) | 574 (38.27) | 0.74 (0.61–0.88) | 0.001 | 1.02 (0.86–1.20) | 0.858 | ||
CC | 90 (11.37) | 90 (8.02) | 113 (7.53) | 0.55 (0.41–0.74) | 1.13 × 10− 4 | 0.94 (0.70–1.27) | 0.693 | ||
TC + CC | 434 (54.80) | 519 (46.26) | 687 (45.80) | 0.70 (0.55–0.89) | 0.004 | 0.99 (0.85–1.17) | 0.976 |
HCC-related HBV mutations
Hotspot mutation | CHB (%) | LC (%) | HCC (%) | HCC versus. HBV-infected subjects without HCC | |
---|---|---|---|---|---|
AORa (95% CI) | P value | ||||
In genotype B HBV-infected subjects | |||||
T1753A/C | 6.12 (6/98) | 15.00 (12/80) | 8.14 (14/172) | 0.57 (0.27–1.20) | 0.139 |
A1762T/G1764A | 34.69 (34/98) | 37.50 (30/80) | 60.47 (104/172) | 1.88 (1.19–2.98) | 0.007 |
A1846T | 16.33 (16/98) | 15.00 (12/80) | 36.05 (62/172) | 2.00 (1.16–3.45) | 0.013 |
G1896A | 16.33 (16/98) | 20.00 (16/80) | 43.02 (74/172) | 2.31 (1.36–3.93) | 0.002 |
In genotype C HBV-infected subjects | |||||
C1653T | 14.56 (46/316) | 19.75 (64/324) | 22.86 (198/866) | 1.55 (1.17–2.04) | 0.002 |
T1674C/G | 15.82 (50/316) | 14.81 (48/324) | 24.25 (210/866) | 1.83 (1.38–2.44) | 3.35 × 10− 5 |
T1753A/C | 14.56 (46/316) | 13.58 (44/324) | 21.94 (190/866) | 1.89 (1.40–2.53) | 2.47 × 10− 5 |
A1762T/G1764A | 42.41 (134/316) | 46.91 (152/324) | 60.97 (528/866) | 2.09 (1.51–2.91) | 1.13 × 10− 5 |
G1719T | 36.08 (114/316) | 39.51 (128/324) | 44.57 (386/866) | 1.39 (1.06–1.83) | 0.017 |
A1846T | 15.82 (50/316) | 14.81 (48/324) | 19.63 (170/866) | 1.53 (1.14–2.06) | 0.005 |
G1896A | 27.85 (88/316) | 15.43 (50/324) | 30.25 (262/866) | 1.93 (1.47–2.54) | 2.60 × 10− 6 |
G1899A | 5.06 (16/316) | 8.02 (26/324) | 15.47 (134/866) | 2.96 (2.03–4.32) | 1.77 × 10− 8 |
preS deletion | 12.66 (40/316) | 18.52 (60/324) | 19.63 (170/866) | 1.77 (1.32–2.39) | 1.53 × 10− 4 |
Associations of HLA-DR genetic polymorphisms with HCC-related HBV mutations
SNPs | Genotype C HBV infected subjects | Genotype B HBV infected subjects | |||||
---|---|---|---|---|---|---|---|
HCC-associated HBV mutation | AORa (95% CI) | P value | HCC-associated HBV mutation | AORa (95% CI) | P value | ||
rs3135363 | |||||||
AA | Reference | Reference | |||||
AG | T1753A/C | 0.33 (0.12–0.96) | 0.042 | ||||
G1896A | 0.20 (0.07–0.59) | 0.003 | |||||
rs9268644 | |||||||
CC | Reference | Reference | |||||
CA | T1674C/G | 0.40 (0.24–0.68) | 0.001 | T1753A/C | 0.34 (0.12–0.65) | 0.033 | |
A1762T/G1764A | 0.51 (0.28–0.92) | 0.025 | |||||
G1899A | 0.43 (0.23–0.82) | 0.010 | |||||
preS deletion | 0.55 (0.31–0.96) | 0.036 | |||||
AA | C1653T | 0.39 (0.16–0.95) | 0.038 | ||||
T1753A/C | 0.33 (0.12–0.90) | 0.030 | |||||
rs35445101 | |||||||
AA | Reference | Reference | |||||
AG | C1653T | 0.33 (0.15–0.75) | 0.008 | ||||
A1762T/G1764A | 0.37 (0.16–0.85) | 0.019 | |||||
GG | C1653T | 0.44 (0.21–0.93) | 0.033 | ||||
G1719T | 0.37 (0.18–0.76) | 0.007 | |||||
G1896A | 0.44 (0.21–0.89) | 0.023 | |||||
rs24755213 | |||||||
AA | Reference | ||||||
AG | C1653T | 0.58 (0.38–0.88) | 0.010 | T1753A/C | 0.26 (0.08–0.91) | 0.035 | |
T1674C/G | 0.45 (0.29–0.69) | 3.23 × 10− 4 | |||||
G1719T | 0.65 (0.43–0.97) | 0.035 | |||||
A1762T/G1764A | 0.50 (0.32–0.79) | 0.003 | |||||
A1846T | 0.63 (0.39–0.99) | 0.046 | |||||
G1899A | 0.36 (0.21–0.61) | 1.32 × 10− 4 | |||||
preS deletion | 0.47 (0.29–0.75) | 0.002 | |||||
GG | T1753A/C | 0.33 (0.17–0.67) | 0.002 | ||||
A1846T | 0.35 (0.16–0.75) | 0.007 | |||||
preS deletion | 0.49 (0.25–0.97) | 0.040 | |||||
rs984778 | |||||||
TT | |||||||
TC | C1653T | 0.37 (0.23–0.60) | 4.15 × 10− 5 | ||||
T1674C/G | 0.34 (0.22–0.54) | 4.00 × 10− 6 | |||||
G1719T | 0.46 (0.30–0.70) | 3.01 × 10− 4 | |||||
T1753A/C | 0.54 (0.35–0.85) | 0.007 | |||||
A1762T/G1764A | 0.61 (0.37–0.99) | 0.046 | |||||
A1846T | 0.58 (0.36–0.92) | 0.021 | |||||
G1896A | 0.51 (0.33–0.79) | 0.002 | |||||
G1899A | 0.30 (0.16–0.55) | 9.56 × 10− 5 |