Associations between AQP1 SNPs and non-haematological side effects of cisplatin based treatment (N = 176)
| Alopeciaa | Nephrotoxicityb | Nausea/Vomitingc | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Genotype | N (%) | OR (95% CI) | P | N (%) | OR (95% CI) | P | N (%) | OR(95% CI) | P |
| GG | 60 (45.8) | Ref. | - | 74 (46.8) | Ref. | - | 73 (53.7) | Ref. | - | |
| rs28362731 | GA | 5 (55.6) | 1.48 (0.38–5.76) | 0.572 | 3 (27.3) | 0.43 (0.11–1.66) | 0.219 | 5 (55.6) | 1.08 (0.28–4.19) | 0.913 |
| GG | 30 (46.2) | Ref. | - | 35 (43.8) | Ref. | - | 36 (52.9) | Ref. | - | |
| GC | 20 (35.7) | 0.65 (0.31–1.35) | 0.246 | 34 (50.0) | 1.29 (0.67–2.46) | 0.448 | 26 (44.8) | 0.72 (0.36–1.46) | 0.364 | |
| rs1049305 | CC | 15 (71.4) | 2.92 (1.00–8.46) | 0.049 | 10 (43.5) | 0.99 (0.39–2.52) | 0.982 | 15 (71.4) | 2.22 (0.77–6.41) | 0.140 |
| GC+CC | 35 (45.5) | 0.97 (0.50–1.89) | 0.934 | 44 (48.4) | 1.20 (0.66–2.20) | 0.547 | 41 (51.9) | 0.96 (050–1.84) | 0.900 |
Clinical characteristics of MM patients treated with cisplatin based chemotherapy (N = 194)
| Characteristic | N (%) | |
|---|---|---|
| Gemcitabine and cisplatin | 132 (68.0) | |
| Chemotherapy type | Pemetrexed and cisplatin | 62 (32.0) |
| Complete response (CR) | 6 (3.2) | |
| Partial response (PR) | 61 (32.8) | |
| Chemotherapy responsea | Stable disease (SD) | 92 (49.5) |
| Progressive disease (PD) | 27 (14.5) | |
| Progression of diseaseb | No | 20 (10.5) |
| Yes | 171 (89.5) | |
| No | 58 (29.9) | |
| Death | Yes | 136 (70.1) |
| PFS | Median (25%–75%) (month) | 7.8 (5.3–13.8) |
| OS | Median (25%–75%) (month) | 18.1 (9.4–28.7) |
| Follow-chemotherapy up from the start of | Median (25%–75%) (month) | 49.2 (18.9–75.5) |
| CRP | Median (25%–75%) | 20.5 (9–58) |
| LDH | Median (25%–75%) | 2.67 (2.26–3.11) |
| Painb | No | 79 (41.4) |
| Yes | 112 (58.6) | |
| No | 68 (35.8) | |
| Weight lossc | Yes | 122 (64.2) |
Influence of interactions on the risk of occurrence of side effects
| Interaction 1rs28362731 | Interaction 2 | Interaction 3 | ||||
|---|---|---|---|---|---|---|
| Side effect | -rs1049305 | P1 | rs28362731 - smoking | P2 | rs1049305 - smoking | P3 |
| OR (95% CI) | OR (95% CI) | OR (95% CI) | ||||
| Anemia grade ≥ 2a | 1.84 (0.10–32.37) | 0.676 | - | 0.999 | 0.34 (0.10–1.16) | 0.085 |
| Leukopenia grade ≥ 2b | 0.95 (0.04–23.07) | 0.974 | - | 0.999 | 0.92 (0.21–4.02) | 0.915 |
| Neutropenia grade ≥ 2 | 0.55 (0.03–9.76) | 0.686 | 7.55 (0.39–145.1) | 0.180 | 0.67 (0.19–2.35) | 0.526 |
| Thrombocytopeniac | 1.73 (0.11–26.38) | 0.693 | 3.06 (0.20–46.56) | 0.422 | 0.95 (0.16–5.66) | 0.955 |
| Nephrotoxicityc | 0.68 (0.04–11.98) | 0.794 | - | 0.999 | 1.01 (0.30–3.43) | 0.982 |
| Alopeciad | 2.06 (0.11–40.01) | 0.633 | - | 0.999 | 0.60 (0.16–2.29) | 0.453 |
| Nausea/Vomitinge | 2.12 (0.11–40.98) | 0.620 | 6.83 (0.35–132.4) | 0.204 | 0.71 (0.19–2.64) | 0.608 |
Influence of AQP1 SNP on survival and chemotherapy response in MM patients
| Progress free | survival | Overall survival | Chemotherapy response | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Genotype | PFS median (25%–75%) month | HR (95% CI) | P | OS median (25%–75%) month | HR (95% CI) | P | Poor response N (%) | Good response N (%) | OR (95% CI) | P |
| GG | 7.7 (5.2–13.6) | Ref. | - | 18.1 (9.1–28.0) | Ref. | - | 112 (65.1) | 60 (34.9) | Ref. | - | |
| rs28362731 | GA | 11.1 (7.0–14.7) | 0.72 (0.39–1.33) | 0.299 | 26.5 (14.4–47.8) | 0.56 (0.26–1.19) | 0.130 | 6 (54.5) | 5 (45.5) | 1.56 (0.46–5.31) | 0.481 |
| GG | 7.9 (5.4–12.1) | Ref. | - | 18.1 (9.0–26.8) | Ref. | - | 55 (64.7) | 30 (35.3) | Ref. | - | |
| GC | 7.8 (5.2–15.0) | 0.80 (0.58–1.11) | 0.187 | 22.1 (10.1–29.7) | 0.72 (0.50–1.05) | 0.091 | 43 (58.1) | 31 (41.9) | 1.32 (0.70–2.51) | 0.394 | |
| rs1049305 | CC | 7.4 (4.8–14.1) | 0.92 (0.59–1.46) | 0.736 | 13.3 (8.1–25.4) | 1.10 (0.67–1.80) | 0.712 | 20 (76.9) | 6 (23.1) | 0.55 (0.20–1.52) | 0.248 |
| GC+CC | 7.8 (4.9–15.0) | 0.83 (0.62–1.13) | 0.233 | 18.2 (9.5–28.7) | 0.81 (0.58–1.14) | 0.220 | 63 (63.0) | 37 (37.0) | 1.08 (0.59–1.97) | 0.810 | |
Association between AQP1 SNPs and haematological side effects of cisplatin based treatment (N = 176)
| Anemia grade ≥ 2a | Thrombocytopeniab | Leukopenia grade ≥ 2c | Neutropenia grade ≥ 2 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Genotype | N (%) | OR (95% CI) | P | OR (95% CI)adj1 | P adj1 | N (%) | OR P (95% CI) | OR (95% CI)adj2 | Padj2 | N OR (%) (95% CI) | P | N (%) | OR P (95% CI) | |
| rs28362731 | GG | 79 (49.4) | Ref. | - | Ref. | - | 21 (13.3) | Ref. - | Ref. | - | 39 Ref. (25.2) | - | 59 (36.4) | Ref. - | |
| GA | 3 (27.3) | (0.100.38 –1.50) | 0.169 | (0.130.53 –2.12) | 0.370 | (36.44 ) | (1.003.73 –13.84) 0.049 | (1.134.63 –19.05) | 0.034 | (18.22 ) (0.140.66 –3.19) | 0.606 | 3 (27.3) | (0.170.66 –2.56) 0.543 | ||
| GG | (56.846 ) | Ref. | - | Ref. | - | (12.510 ) | Ref. - | Ref. | - | (14 17.5) Ref. | - | 25 (30.9) | Ref. - | ||
| GC | (34.323 ) | (0.200.40 –0.78) | 0.007 | (0.230.46 –0.92) | 0.029 | (11.88 ) | (0.350.93 –2.52) 0.892 | (0.240.71 –1.08) | 0.529 | (18 27.7) (0.821.81 –3.99) | 0.144 | 26 (37.1) | (0.671.32 –2.60) 0.416 | ||
| rs1049305 | CC | (52.013 ) | (0.340.82 –2.03) | 0.674 | (0.280.74 –1.94) | 0.536 | (30.47 ) | (1.013.06 –9.28) 0.048 | (0.692.18 –6.94) | 0.185 | (36.19 ) (1.103.03 –8.38) | 0.033 | 11 (45.8) | (0.751.90 –4.81) 0.178 | |
| GC +CC | (39.136 ) | (0.270.49 –0.90) | 0.021 | (0.270.52 –0.99) | 0.046 | (16.515 ) | (0.581.38 –3.28) 0.463 | (0.431.07 –2.69) | 0.885 | (30.727 ) (1.002.09 –4.35) | 0.049 | 37 (39.4) | (0.781.45 –2.72) 0.242 | ||
Description of all malignant mesothelioma (MM) patients (N = 231) and MM patients treated with cisplatin based chemotherapy (N = 194)
| All MM patients | MM patients cisplatin treated based with chemotherapy | ||
|---|---|---|---|
| Characteristic | Characteristic type | N (%) | N (%) |
| Age | Median (25%–75%) | 66 (58–73) | 65 (58–71.3) |
| Gender | Men | 170 (73.6) | 146 (75.3) |
| Women | 61 (26.4) | 48 (24.7) | |
| I | 18 (7.8) | 15 (7.7) | |
| II | 57 (24.7) | 48 (24.7) | |
| MM stage | III IV | 69 (29.9) 66 (28.6) | 62 (32.0) 50 (25.8) |
| Peritoneal MM | 20 (8.7) | 18 (9.3) | |
| Undefined | 1 (0.4) | 1 (0.5) | |
| Epithelioid | 167 (72.3) | 147 (75.8) | |
| Histological | Biphasic | 26 (11.3) | 21 (10.8) |
| type | Sarcomatoid | 24 (10.4) | 21 (10.8) |
| Undefined | 14 (6.0) | 5 (2.6) | |
| 0 | 15 (6.5) | 15 (7.7) | |
| ECOG | 1 | 111 (48.1) | 100 (51.5) |
| performance status | 2 | 90 (39.0) | 76 (39.2) |
| 3 | 15 (6.5) | 3 (1.5) | |
| Exposure to | No | 59 (26.6)a | 45 (23.3)c |
| asbestos | Yes | 166 (73.8) | 148 (76.7) |
| No | 120 (53.3)a | 101(52.6)d | |
| Smoking | Yes | 105 (46.7) | 91(47.4) |
| Gemcitabine/ Cisplatin | 132 (60.0)b | 132 (68.0) | |
| Pemetrexed/Cisplatin | 62 (28.2) | 62 (32.0) | |
| Treatment | chemotherapy Without | 16 (7.3) | - |
| Other forms of chemotherapy | 10 (4.5) | - |
Distribution of AQP1 genotypes in MM patients and controls and risk of MM
| Patients | Controls | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Role | Genotype | N (%) | MAF | PHWE | N (%) | MAF | PHWE | OR (95% CI) | P | OR (95% CI)adj | Padj |
| rs28362731a | p.Gly165Asp | GG | 210 (92.1) | 0.039 | 0.535 | 288 (91.7) | 0.041 | 0.444 | Ref. | - | Ref. | - |
| GA | 18 (7.9) | 26 (8.3) | 0.95 | 0.871 | 0.94 | 0.885 | ||||||
| (0.51–1.78) | (0.38–2.30) | |||||||||||
| rs1049305b | c.*578G>C | GG | 107 (46.5) | 0.337 | 0.082 | 128 (40.8) | 0.373 | 0.288 | Ref. | - | Ref. | - |
| GC | 91 (39.6) | 138 (43.9) | 0.79 | 0.207 | 0.59 | 0.039 | ||||||
| (0.55–1.14) | (0.35–0.97) | |||||||||||
| CC | 32 (13.9) | 48 (15.3) | 0.80 | 0.390 | 0.63 | 0.199 | ||||||
| (0.48–1.13) | (0.32–1.27) | |||||||||||
| GC+CC | 123 (53.5) | 186 (59.2) | 0.79 | 0.181 | 0.60 | 0.033 | ||||||
| (0.56–1.12) | (0.37–0.96) | |||||||||||
| rs1476597c | c.-783G>C | GG | 157 (68.0) | 0.255 | <0.001 | 220 (70.1) | 0.247 | <0.001 | ||||
| GC | 30 (13.0) | 33 (10.5) | ||||||||||
| CC | 44 (19.0) | 61 (19.4) |