Background
Methods
Patients
SNP selection
HCV genotyping and RNA measurements
Genomic DNA extraction and genotyping
Statistical analysis
Results
Patient characteristics
HCV genotype 1 (HCV-1) | HCV genotype 2 (HCV-2) | |||||||
---|---|---|---|---|---|---|---|---|
Total | RVR (+) | RVR (−) |
Pvalue | Total | RVR (+) | RVR (−) |
Pvalue | |
Number of patients | 265 | 108 | 157 | - | 195 | 158 | 37 | - |
Sex (males/females) | 129/136 | 55/53 | 74/83 | 0.545 | 88/107 | 75/83 | 13/24 | 0.176 |
Age (mean ± SD) | 52.17 ± 10.27 | 50.96 ± 10.97 | 52.99 ± 9.71 | 0.172a
| 51.62 ± 10.89 | 51.08 ± 10.92 | 53.89 ± 10.62 | 0.095a
|
BMI (mean ± SD) | 24.6 ± 3.1 | 24.6 ± 3.0 | 24.6 ± 3.2 | 0.971a
| 24.5 ± 3.5 | 24.5 ± 3.7 | 24.5 ± 3.1 | 0.933a
|
Degree of inflammatory activity (A0/A1-3) | 35/230 | 10/98 | 25/132 | 0.115b
| 22/173 | 19/139 | 3/34 | 0.498 b
|
Stage of fibrosis (F0/F1-4) | 16/249 | 3/105 | 13/144 | 0.065 b
| 10/185 | 9/149 | 1/36 | 0.457 b
|
AST (U/L) (mean ± SD) | 83.5 ± 57.1 | 80.7 ± 45.1 | 0.988 a
| 85.7 ± 65.5 | 75.2 ± 39.1 | 0.677 a
| ||
ALT (U/L) (mean ± SD) | 132.2 ± 93.5 | 102.4 ± 57.6 | 0.018 a
| 122.9 ± 108 | 101.9 ± 60.7 | 0.329 a
| ||
PLT (×103/μl) (mean ± SD) | 174.6 ± 62.3 | 163.7 ± 55.7 | 0.146 a
| 173.6 ± 53.5 | 155.5 ± 50.1 | 0.041 a
| ||
Viral load (× 106) | 12.1 ± 16.4 | 7.0 ± 10.3 | 16.0 ± 18.8 | <0.0001a
| 11.0 ± 19.0 | 10.0 ± 18.2 | 15.3 ± 21.8 | 0.217a
|
SNP | Position inGNB1
| Chromosome positiona
| Alleles | HCV-1 | HCV-2 | ||||
---|---|---|---|---|---|---|---|---|---|
HWE (Pvalue) | MAF | HWE (Pvalue) | MAF | ||||||
RVR (+) | RVR (−) | RVR (+) | RVR (−) | ||||||
rs10907185 (S1) | Intron 7 | 1733219 | A/G | 0.2132 | 0.3009 | 0.2548 | 0.465 | 0.2785 | 0.2162 |
rs6603797 (S2) | Intron 2 | 1765583 | C/T | 0.5854 | 0.1065 | 0.1401 | 0.4007 | 0.0981 | 0.0946 |
rs4648727 (S3) | Intron 1 | 1776269 | A/C | 0.1309 | 0.3241 | 0.3429 | 0.8709 | 0.3513 | 0.2361 |
rs12126768 (S4) | Intron 1 | 1778090 | G/T | 0.7439 | 0.2083 | 0.2756 | 1 | 0.2373 | 0.2162 |
Association between tagging SNPs of GNB1and therapeutic response, RVR
HCV-1 | HCV-2 | ||||||||
---|---|---|---|---|---|---|---|---|---|
SNP ID | RVR (+) (N = 108) N (%) | RVR (−) (N = 157) N (%) |
Pvalue | OR (95% CI) | SNP ID | RVR (+) (N = 158) N (%) | RVR (−) (N = 37) N (%) |
Pvalue | OR (95% CI) |
rs10907185
|
rs10907185
| ||||||||
A/A | 10 (9.2) | 5 (3.2) | 3.09 (1.00, 9.56) | A/A | 13 (8.3) | 3 (8.1) | 1.25 (0.33, 4.76) | ||
A/G | 45 (41.7) | 70 (44.6) | 0.99 (0.60, 1.66) | A/G | 62 (39.2) | 10 (27.0) | 1.79 (0.80, 4.02) | ||
G/G | 53 (49.1) | 82 (52.2) | 0.1096 | 1 | G/G | 83 (52.5) | 24 (64.9) | 0.3601 | 1 |
A/A + A/G | 55 (50.9) | 75 (47.8) | 0.6137 | 1.13 (0.69, 1.85) | A/A + A/G | 75 (47.5) | 13 (35.1) | 0.1748 | 1.67 (0.79, 3.51) |
rs6603797
|
rs6603797
| ||||||||
C/C | 87 (80.5) | 116 (73.9) | 1.13 (0.18, 6.88) | C/C | 129 (81.6) | 31 (83.8) | 2.08 (0.18, 23.69) | ||
C/T | 19 (17.6) | 38 (24.2) | 0.75 (0.12, 4.88) | C/T | 27 (17.1) | 5 (13.5) | 2.70 (0.20, 35.75) | ||
T/T | 2 (1.9) | 3 (1.9) | 0.4332 | 1 | T/T | 2 (1.3) | 1 (2.7) | 0.7216 | 1 |
C/C + C/T | 106 (98.1) | 154 (98.1) | 0.9723 | 1.03 (0.17, 6.29) | C/C + C/T | 156 (98.7) | 36 (97.3) | 0.5227 | 2.17 (0.19, 24.55) |
rs4648727
a
|
rs4648727
a
| ||||||||
A/A | 10 (9.3) | 14 (9.0) | 0.94 (0.38, 2.29) | A/A | 16 (10.1) | 4 (11.1) | 1.46 (0.44, 4.83) | ||
A/C | 50 (46.3) | 79 (50.6) | 0.83 (0.50, 1.39) | A/C | 79 (50.0) | 9 (25.0) | 3.20 (1.39, 7.41) | ||
C/C | 48 (44.4) | 63 (40.4) | 0.7779 | 1 | C/C | 63 (39.9) | 23 (63.9) | 0.0194* | 1 |
A/A + A/C | 60 (55.6) | 93 (59.6) | 0.5112 | 0.86 (0.52, 1.41) | A/A + A/C | 95 (60.1) | 13 (36.1) | 0.0089* | 2.67 (1.26, 5.65) |
rs12126768
a
|
rs12126768
| ||||||||
G/G | 6 (5.5) | 9 (5.8) | 0.76 (0.26, 2.25) | G/G | 6 (3.8) | 4 (10.8) | 0.42 (0.11, 1.61) | ||
G/T | 33 (30.6) | 68 (43.6) | 0.56 (0.33, 0.94) | G/T | 63 (39.9) | 8 (21.6) | 2.21 (0.94, 5.22) | ||
T/T | 69 (63.9) | 79 (50.6) | 0.0891 | 1 | T/T | 89 (56.3) | 25 (67.6) | 0.0436* | 1 |
G/G + G/T | 39 (36.1) | 77 (49.4) | 0.0330* | 0.58 (0.35, 0.96) | G/G + G/T | 69 (43.7) | 12 (32.4) | 0.2118 | 1.62 (0.76, 3.44) |
HCV-1 | HCV-2 | ||||||||
---|---|---|---|---|---|---|---|---|---|
SNP ID | RVR (+) (N = 108) N (%) | RVR (−) (N = 157) N (%) |
Pvalue | OR (95% CI) | SNP ID | RVR (+) (N = 158) N (%) | RVR (−) (N = 37) N (%) |
Pvalue | OR (95% CI) |
rs10907185
|
rs10907185
| ||||||||
A allele | 65 (30.0) | 80 (25.5) | 1.26 (0.86, 1.85) | A allele | 88 (27.8) | 16 (21.6) | 1.40 (0.76, 2.56) | ||
G allele | 151 (70.0) | 234 (74.5) | 0.2416 | 1 | G allele | 228 (72.2) | 58 (78.4) | 0.2756 | 1 |
rs6603797
|
rs6603797
| ||||||||
C allele | 193 (89.4) | 270 (86.0) | 1.37 (0.80, 2.34) | C allele | 285 (90.2) | 67 (90.5) | 0.96 (0.41, 2.28) | ||
T allele | 23 (10.6) | 44 (14.0) | 0.2521 | 1 | T allele | 31 (9.8) | 7 (9.5) | 0.9270 | 1 |
rs4648727
a
|
rs4648727
a
| ||||||||
A allele | 70 (32.4) | 107 (34.3) | 0.92 (0.64, 1.33) | A allele | 111 (35.1) | 17 (23.6) | 1.75 (0.97, 3.16) | ||
C allele | 146 (67.6) | 205 (65.7) | 0.6515 | 1 | C allele | 205 (64.9) | 55 (76.4) | 0.0607 | 1 |
rs12126768
a
|
rs12126768
| ||||||||
G allele | 45 (20.8) | 86 (27.6) | 0.69 (0.46, 1.04) | G allele | 75 (23.7) | 16 (21.6) | 1.13 (0.61, 2.08) | ||
T allele | 171 (79.2) | 226 (72.4) | 0.0783 | 1 | T allele | 241 (76.3) | 58 (78.4) | 0.6989 | 1 |
HCV-1 | HCV-2 | ||||||||
---|---|---|---|---|---|---|---|---|---|
SNP ID | RVR (+) N (%) | RVR (−) N (%) |
Pvalue | OR (95% CI) | SNP ID | RVR (+) N (%) | RVR (−) N (%) |
Pvalue | OR (95% CI) |
rs10907185
|
rs10907185
| ||||||||
Males
|
Males
| ||||||||
A/A | 6 (10.9) | 2 (2.8) | 4.32 (0.81, 23.17) | A/A | 8 (10.7) | 0 (0.0) | - | ||
A/G | 24 (43.6) | 36 (48.6) | 0.96 (0.46, 1.98) | A/G | 27 (36.0) | 6 (46.2) | 0.79 (0.24, 2.60) | ||
G/G | 25 (45.5) | 36 (48.6) | 0.1600 | 1 | G/G | 40 (53.3) | 7 (53.8) | 0.4292 | 1 |
A/A + A/G | 30 (54.5) | 38 (51.4) | 0.7193 | 1.14 (0.56, 2.29) | A/A + A/G | 35 (46.7) | 6 (46.2) | 0.9727 | 1.02 (0.31, 3.33) |
Females
|
Females
| ||||||||
A/A | 4 (7.6) | 3 (3.6) | 2.19 (0.46, 10.52) | A/A | 5 (6.0) | 3 (12.5) | 0.66 (0.14, 3.07) | ||
A/G | 21 (39.6) | 34 (41.0) | 1.01 (0.49, 2.08) | A/G | 35 (42.2) | 4 (16.7) | 3.46 (1.07, 11.22) | ||
G/G | 28 (52.8) | 46 (55.4) | 0.5986 | 1 | G/G | 43 (51.8) | 17 (70.8) | 0.0618 | 1 |
A/A + A/G | 25 (47.2) | 37 (44.6) | 0.7673 | 1.11 (0.56, 2.22) | A/A + A/G | 40 (48.2) | 7 (29.2) | 0.0981 | 2.26 (0.85, 6.02) |
rs6603797
|
rs6603797
| ||||||||
Males
|
Males
| ||||||||
C/C | 45 (81.8) | 50 (67.6) | - | C/C | 60 (80.0) | 12 (92.3) | - | ||
C/T | 9 (16.4) | 24 (32.4) | - | C/T | 15 (20.0) | 1 (7.7) | - | ||
T/T | 1 (1.8) | 0 (0.0) | 0.0672 | 1 | T/T | 0 (0.0) | 0 (0.0) | - | 1 |
C/C + C/T | 54 (98.2) | 74 (100.0) | 0.2442 | - | C/C + C/T | 75 (100.0) | 13 (100.0) | - | - |
Females
|
Females
| ||||||||
C/C | 42 (79.2) | 66 (79.5) | 1.91 (0.19, 18.97) | C/C | 69 (83.1) | 19 (79.2) | 1.82 (0.16, 21.12) | ||
C/T | 10 (18.9) | 14 (16.9) | 2.14 (0.19, 23.72) | C/T | 12 (14.5) | 4 (16.6) | 1.50 (0.11, 21.31) | ||
T/T | 1 (1.9) | 3 (3.6) | 0.8179 | 1 | T/T | 2 (2.4) | 1 (4.2) | 0.8601 | 1 |
C/C + C/T | 52 (98.1) | 80 (96.4) | 0.5609 | 1.95 (0.20, 19.26) | C/C + C/T | 81 (97.6) | 23 (95.8) | 0.6461 | 1.76 (0.15, 20.30) |
rs4648727
|
rs4648727
| ||||||||
Males
|
Males
a
| ||||||||
A/A | 4 (7.3) | 5 (6.8) | 1.20 (0.29, 5.02) | A/A | 9 (12.0) | 0 (0.0) | - | ||
A/C | 31 (56.4) | 39 (52.7) | 1.19 (0.57, 2.49) | A/C | 39 (52.0) | 5 (41.7) | 2.02 (0.58, 7.05) | ||
C/C | 20 (36.3) | 30 (40.5) | 0.8905 | 1 | C/C | 27 (36.0) | 7 (58.3) | 0.2255 | 1 |
A/A + A/C | 35 (63.6) | 44 (59.5) | 0.6301 | 1.19 (0.58, 2.45) | A/A + A/C | 48 (64.0) | 5 (41.7) | 0.1410 | 2.49 (0.72, 8.61) |
Females
a
|
Females
| ||||||||
A/A | 6 (11.4) | 9 (11.0) | 0.79 (0.25, 2.48) | A/A | 7 (8.4) | 4 (16.7) | 0.78 (0.20, 3.04) | ||
A/C | 19 (35.8) | 40 (48.8) | 0.56 (0.27, 1.18) | A/C | 40 (48.2) | 4 (16.7) | 4.44 (1.36, 14.53) | ||
C/C | 28 (52.8) | 33 (40.2) | 0.3067 | 1 | C/C | 36 (43.4) | 16 (66.6) | 0.0202* | 1 |
A/A + A/C | 25 (47.2) | 49 (59.8) | 0.1513 | 0.60 (0.30, 1.21) | A/A + A/C | 47 (56.6) | 8 (33.3) | 0.0443* | 2.61 (1.01, 6.77) |
rs12126768
|
rs12126768
| ||||||||
Males
|
Males
| ||||||||
G/G | 3 (5.5) | 3 (4.1) | 1.06 (0.20, 5.59) | G/G | 2 (2.7) | 0 (0.0) | - | ||
G/T | 17 (30.9) | 34 (45.9) | 0.53 (0.25, 1.11) | G/T | 31 (41.3) | 4 (30.8) | 1.66 (0.47, 5.89) | ||
T/T | 35 (63.6) | 37 (50.0) | 0.2244 | 1 | T/T | 42 (56.0) | 9 (69.2) | 0.6089 | 1 |
G/G + G/T | 20 (36.4) | 37 (50.0) | 0.1230 | 0.57 (0.28, 1.17) | G/G + G/T | 33 (44.0) | 4 (30.8) | 0.3723 | 1.77 (0.50, 6.25) |
Females
a
|
Females
| ||||||||
G/G | 3 (5.7) | 6 (7.3) | 0.62 (0.14, 2.65) | G/G | 4 (4.8) | 4 (16.7) | 0.34 (0.08, 1.52) | ||
G/T | 16 (30.2) | 34 (41.5) | 0.58 (0.28, 1.23) | G/T | 32 (38.6) | 4 (16.7) | 2.72 (0.83, 8.90) | ||
T/T | 34 (64.1) | 42 (51.2) | 0.3339 | 1 | T/T | 47 (56.6) | 16 (66.6) | 0.0350* | 1 |
G/G + G/T | 19 (35.8) | 40 (48.8) | 0.1391 | 0.59 (0.29, 1.19) | G/G + G/T | 36 (43.4) | 8 (33.4) | 0.3786 | 1.53 (0.59, 3.97) |
HCV-1 | HCV-2 | ||||||||
---|---|---|---|---|---|---|---|---|---|
SNP ID | RVR (+) N (%) | RVR (−) N (%) |
Pvalue | OR (95% CI) | SNP ID | RVR (+) N (%) | RVR (−) N (%) |
Pvalue | OR (95% CI) |
Males
| |||||||||
rs10907185
|
rs10907185
| ||||||||
A allele | 36 (32.7) | 40 (27.0) | 1.31 (0.77, 2.25) | A allele | 43 (28.7) | 6 (23.1) | 1.34 (0.50, 3.56) | ||
G allele | 74 (67.3) | 108 (73.0) | 0.3206 | 1 | G allele | 107 (71.3) | 20 (76.9) | 0.5572 | 1 |
rs6603797
|
rs6603797
| ||||||||
C allele | 99 (90.0) | 124 (83.8) | 1.74 (0.81, 3.73) | C allele | 135 (90.0) | 25 (96.2) | 0.36 (0.05, 2.85) | ||
T allele | 11 (10.0) | 24 (16.2) | 0.1493 | 1 | T allele | 15 (10.0) | 1 (3.8) | 0.3136 | 1 |
rs4648727
|
rs4648727
a
| ||||||||
A allele | 39 (35.5) | 49 (33.1) | 1.11 (0.66, 1.87) | A allele | 57 (38.0) | 5 (20.8) | 2.33 (0.82, 6.58) | ||
C allele | 71 (64.5) | 99 (66.9) | 0.6942 | 1 | C allele | 93 (62.0) | 19 (79.2) | 0.1030 | 1 |
rs12126768
|
rs12126768
| ||||||||
G allele | 23 (20.9) | 40 (27.0) | 0.71 (0.40, 1.28) | G allele | 35 (23.3) | 4 (15.4) | 1.67 (0.54, 5.18) | ||
T allele | 87 (79.1) | 108 (73.0) | 0.2580 | 1 | T allele | 115 (76.7) | 22 (84.6) | 0.3676 | 1 |
Females
| |||||||||
rs10907185
|
rs10907185
| ||||||||
A allele | 29 (27.4) | 40 (24.1) | 1.19 (0.68, 2.07) | A allele | 45 (27.1) | 10 (20.8) | 1.41 (0.65, 3.07) | ||
G allele | 77 (72.6) | 126 (75.9) | 0.5465 | 1 | G allele | 121 (72.9) | 38 (79.2) | 0.3809 | 1 |
rs6603797
|
rs6603797
| ||||||||
C allele | 94 (88.7) | 146 (88.0) | 1.07 (0.50, 2.30) | C allele | 150 (90.4) | 42 (87.5) | 1.34 (0.49, 3.64) | ||
T allele | 12 (11.3) | 20 (12.0) | 0.8559 | 1 | T allele | 16 (9.6) | 6 (12.5) | 0.5653 | 1 |
rs4648727
a
|
rs4648727
| ||||||||
A allele | 31 (29.2) | 58 (35.4) | 0.76 (0.45, 1.28) | A allele | 54 (32.5) | 12 (25.0) | 1.45 (0.70, 3.00) | ||
C allele | 75 (70.8) | 106 (64.6) | 0.2961 | 1 | C allele | 112 (67.5) | 36 (75.0) | 0.3198 | 1 |
rs12126768
a
|
rs12126768
| ||||||||
G allele | 22 (20.8) | 46 (28.0) | 0.67 (0.38, 1.20) | G allele | 40 (24.1) | 12 (25.0) | 0.95 (0.45, 2.00) | ||
T allele | 84 (79.2) | 118 (72.0) | 0.1776 | 1 | T allele | 126 (75.9) | 36 (75.0) | 0.8977 | 1 |
Frequencies of GNB1haplotypes and their association with RVR
Sliding window (SW) | Most significant result | ||||
---|---|---|---|---|---|
HCV Genotype | |||||
1 | 2 | 1 | 2 | ||
SNPs/SW
|
No. of SW
|
SW
|
SW
|
P
value
|
P
value
|
1 | 4 | - | - | - | - |
2 | 3 | S1.S2 | S3.S4 | 0.0208* | 0.0546 |
3 | 2 | S2.S4 | S2.S4 | 0.0540 | 0.1099 |
4 | 1 | S1.S4 | S1.S4 | 0.0397* | 0.1585 |
HCV-1 | ||||
---|---|---|---|---|
Haplotypes | RVR (+) | RVR (−) | OR |
Pvalue |
rs10907185-rs6603797 (S1-S2) | ||||
OMNIBUS | - | - | - | 0.0208* |
AC | 0.2 | 0.1158 | 1.91 | 0.0078* |
rs6603797-rs4648727-rs12126768 (S2-S3-S4) | ||||
OMNIBUS | - | - | - | 0.054 |
CAT | 0.1157 | 0.0673 | 1.81 | 0.0524 |
rs10907185-rs6603797-rs4648727-rs12126768 (S1-S2-S3-S4) | ||||
OMNIBUS | - | - | - | 0.0397* |
ACAT | 0.1163 | 0.0615 | 2.01 | 0.0261* |
HCV-2
| ||||
Haplotypes
|
RVR (+)
|
RVR (−)
|
OR
|
P
value
|
rs4648727-rs12126768 (S3-S4) | ||||
OMNIBUS | - | - | - | 0.0546 |
AT | 0.1139 | 0.0278 | 4.50 | 0.0265* |
rs6603797-rs4648727-rs12126768 (S2-S3-S4) | ||||
OMNIBUS | - | - | - | 0.1099 |
CAT | 0.1139 | 0.0278 | 4.50 | 0.0265* |
rs10907185-rs6603797-rs4648727-rs12126768 (S1-S2-S3-S4) | ||||
OMNIBUS | - | - | - | 0.1585 |
ACAT | 0.1149 | 0.0278 | 4.54 | 0.0253* |