Association of SNPs with lung cancer risk
Four genetic analysis models (co-dominant, dominant, recessive and log-additive) were applied to analyze and assess the association between each variant and lung cancer risks. In Table 3, our analysis revealed the genotype "A/C” of rs6771238 was correlated with an increased the risk of lung cancer under the co-dominant model (OR = 1.57, 95% CI = 1.01–2.42, p = 0.044), the genotype "C/A-A/A" of rs6771238 was correlated with an enhanced lung cancer risk in the dominant mode (OR = 1.68, 95% CI = 1.05–2.68, p = 0.031), with power values of 0.534 and 0.684, respectively. Rs6771238 also reduced lung cancer risk in an additive model (OR = 1.66, 95% CI = 1.06–2.58, p = 0.026), with power values of 0.500.
Table 3
Relationship between SNPs in CMTM8 gene and the risk of lung cancer
SNP | Model | Genotype | Control | Case | Without Adjustment | With Adjustment | Study power |
OR (95% CI) | pa-value | OR (95% CI) | pb-value |
rs9853415 | Codominant | A/A | 136 (26.9%) | 128 (25.1%) | 1 | | 1 | | |
| | A/G | 256 (50.6%) | 273 (53.6%) | 1.13 (0.84–1.52) | 0.407 | 1.16(0.84–1.59) | 0.369 | |
| | G/G | 114 (22.5%) | 108 (21.2%) | 1.01 (0.7–1.44) | 0.971 | 1.13(0.77–1.65) | 0.545 | |
| Dominant | A/A | 136 (26.9%) | 128 (25.1%) | 1 | | 1 | | |
| | A/G-G/G | 370 (73.1%) | 381 (74.9%) | 1.09 (0.83–1.45) | 0.53 | 1.15(0.85–1.55) | 0.371 | |
| Recessive | A/A-A/G | 392 (77.5%) | 401 (78.8%) | 1 | | 1 | | |
| | G/G | 114 (22.5%) | 108 (21.2%) | 0.93 (0.69–1.25) | 0.613 | 1.02(0.74–1.41) | 0.894 | |
| Log-additive | --- | --- | --- | 1.01 (0.84–1.21) | 0.923 | 1.07(0.88–1.29) | 0.518 | |
rs6796318 | Co-dominant | A/A | 426 (84.4%) | 423 (83.1%) | 1 | | 1 | | |
| | A/G | 75 (14.9%) | 80 (15.7%) | 1.07 (0.76–1.51) | 0.682 | 1.06(0.73–1.53) | 0.753 | |
| | G/G | 4 (0.8%) | 6 (1.2%) | 1.51 (0.42–5.39) | 0.525 | 1.90(0.46–7.8) | 0.372 | |
| Dominant | A/A | 426 (84.4%) | 423 (83.1%) | 1 | | 1 | | |
| | A/G-G/G | 79 (15.6%) | 86 (16.9%) | 1.1 (0.79–1.53) | 0.589 | 1.1(0.77–1.57) | 0.61 | |
| Recessive | A/A-A/G | 501 (99.2%) | 503 (98.8%) | 1 | | 1 | | |
| | G/G | 4 (0.8%) | 6 (1.2%) | 1.49 (0.42–5.33) | 0.536 | 1.89(0.46–7.72) | 0.378 | |
| Log-additive | --- | --- | --- | 1.11 (0.81–1.5) | 0.518 | 1.12(0.81–1.56) | 0.492 | |
rs6771238 | Co-dominant | C/C | 467 (92.3%) | 451 (88.6%) | 1 | | 1 | | |
| | C/A | 37 (7.3%) | 56 (11.0%) | 1.57 (1.01–2.42) | 0.043* | 1.57 (1.01–2.42) | 0.044* | 0.534 |
| | A/A | 2 (0.4%) | 2 (0.4%) | 1.04 (0.15–7.38) | 0.972 | 3.29(0.29–36.87) | 0.333 | |
| Dominant | C/C | 467 (92.3%) | 451 (88.6%) | 1 | | 1 | | |
| | C/A-A/A | 39 (7.7%) | 58 (11.4%) | 1.54 (1.01–2.36) | 0.047* | 1.68(1.05–2.68) | 0.031* | 0.684 |
| Recessive | C/C-C/A | 504 (99.6%) | 507 (99.6%) | 1 | | 1 | | |
| | A/A | 2 (0.4%) | 2 (0.4%) | 0.99 (0.14–7.08) | 0.995 | 3.16(0.28–35.38) | 0.35 | |
| Log-additive | --- | --- | --- | 1.47 (0.98–2.19) | 0.062 | 1.66(1.06–2.58) | 0.026* | 0.500 |
rs9835916 | Co-dominant | T/T | 181 (36.9%) | 161 (32.1%) | 1 | | 1 | | |
| | T/C | 226 (46.1%) | 249 (49.7%) | 1.24 (0.94–1.64) | 0.132 | 1.19(0.88–1.62) | 0.254 | |
| | C/C | 83 (16.9%) | 91 (18.2%) | 1.23 (0.86–1.78) | 0.262 | 1.07(0.72–1.59) | 0.722 | |
| Dominant | T/T | 181 (36.9%) | 161 (32.1%) | 1 | | 1 | | |
| | T/C-C/C | 309 (63.1%) | 340 (67.9%) | 1.24 (0.95–1.61) | 0.112 | 1.16(0.87–1.54) | 0.311 | |
| Recessive | T/T-T/C | 407 (83.1%) | 410 (81.8%) | 1 | | 1 | | |
| | C/C | 83 (16.9%) | 91 (18.2%) | 1.09 (0.78–1.51) | 0.612 | 0.97(0.68–1.38) | 0.858 | |
| Log-additive | --- | --- | --- | 1.13 (0.95–1.35) | 0.176 | 1.06(0.87–1.28) | 0.559 | |
rs1077868 | Co-dominant | A/A | 354 (70%) | 344 (67.6%) | 1 | | 1 | | |
| | A/G | 136 (26.9%) | 154 (30.3%) | 1.17 (0.89–1.53) | 0.274 | 0.66(0.29–1.48) | 0.315 | |
| | G/G | 16 (3.2%) | 11 (2.2%) | 0.71 (0.32–1.55) | 0.386 | 1.24(0.92–1.67) | 0.154 | |
| Dominant | A/A | 354 (70%) | 344 (67.6%) | 1 | | 1 | | |
| | A/G-G/G | 152 (30.0%) | 165 (32.4%) | 1.12 (0.86–1.46) | 0.414 | 1.17(0.88–1.56) | 0.28 | |
| Recessive | A/A-A/G | 490 (96.8%) | 498 (97.8%) | 1 | | 1 | | |
| | G/G | 16 (3.2%) | 11 (2.2%) | 0.68 (0.31–1.47) | 0.325 | 0.62(0.28–1.38) | 0.243 | |
| Log-additive | --- | --- | --- | 1.05 (0.83–1.33) | 0.677 | 1.08(0.84–1.38) | 0.568 | |
rs6802418 | Co-dominant | G/G | 248 (49%) | 230 (45.2%) | 1 | | 1 | | |
| | G/A | 209 (41.3%) | 228 (44.8%) | 1.18 (0.91–1.53) | 0.22 | 1.15(0.87–1.53) | 0.32 | |
| | A/A | 49 (9.7%) | 51 (10%) | 1.12 (0.73–1.73) | 0.6 | 1.06(0.66–1.68) | 0.822 | |
| Dominant | G/G | 248 (49%) | 230 (45.2%) | 1 | | 1 | | |
| | G/A-A/A | 258 (51.0%) | 279 (54.8%) | 1.17 (0.91–1.49) | 0.222 | 1.13(0.87–1.48) | 0.355 | |
| Recessive | G/G-G/T | 457 (90.3%) | 458 (90.0%) | 1 | | 1 | | |
| | A/A | 49 (9.7%) | 51 (10.0%) | 1.04 (0.69–1.57) | 0.858 | 0.99(0.63–1.55) | 0.954 | |
| Log-additive | --- | --- | --- | 1.10 (0.91–1.33) | 0.313 | 1.07(0.88–1.31) | 0.497 | |
SNP: Single nucleotide polymorphism; OR: Odds ratio; 95% CI: 95% confidence interval; |
pa-value calculated by logistic regression analysis; |
pb-value calculated by logistic regression analysis with adjustments for gender, age, smoking, and drinking); |
*p-value < 0.05 indicates statistical significance. |
Further, we stratified the samples according to pathological classification, clinical stage, lymph node metastasis and other characteristics. Within the subgroups of lung squamous cell carcinoma and lung adenocarcinoma, the allele “A” of rs6771238 (OR = 1.90, 95% CI = 1.07–3.38, p = 0.025, power = 0.642) showed an increased risk of lung squamous cell carcinoma in the allele model. Rs6771238 also was significantly associated with an increased lung squamous cell carcinoma risk under the log addition model (OR = 1.98, 95% CI = 1.01–3.87, p = 0.045, power = 0.704). Rs6771238 also was significantly correlated with an enhanced adenocarcinoma risk under log-additive model (OR = 1.79, 95% CI = 1.01–3.18, p = 0.047, power = 0.549) (Table 4).
Table 4
Stratified analysis of CMTM8 polymorphism and lung squamous cell carcinoma and lung adenocarcinoma risk in lung cancer case types
SNP | Model | Genotype | Squamous cell carcinoma | | Adenocarcinoma | |
Control | Case | OR (95% CI) | pa-value | Study power | Control | Case | OR (95% CI) | pb-value | Study power |
rs6771238 | Alleles | C | 971 (95.9%) | 224 (92.6%) | 1 | | | 971 (95.9%) | 363 (94.0%) | 1 | | |
| | A | 41 (4.1%) | 18 (7.4%) | 1.90(1.07–3.38) | 0.025* | 0.642 | 41 (4.1%) | 23 (6.0%) | 1.50 (0.89–2.54) | 0.151 | |
| Co-dominant | C/C | 467 (92.3%) | 104 (86.0%) | 1 | | | 467 (92.3%) | 171 (88.6%) | 1 | | |
| | A/C | 37 (7.3%) | 16 (13.2%) | 1.95(0.93–4.12) | 0.078 | | 37 (7.3%) | 21 (10.9%) | 1.66(0.89–3.08) | 0.109 | |
| | A/A | 2 (0.4%) | 1 (0.8%) | 4.35(0.24–77.44) | 0.317 | | 2 (0.4%) | 1 (0.5%) | 7.54(0.45–125.1) | 0.159 | |
| Dominant | C/C | 467 (92.3%) | 104 (86.0%) | 1 | | | 467 (92.3%) | 171 (88.6%) | 1 | | |
| | A/C-A/A | 39 (7.7%) | 17 (14.0%) | 2.04(0.99–4.21) | 0.054 | | 39 (7.7%) | 22 (11.4%) | 1.75(0.95–3.22) | 0.07 | |
| Recessive | C/C-A/C | 504 (99.6%) | 120 (99.2%) | 1 | | | 504 (99.6%) | 192 (99.5%) | 1 | | |
| | A/A | 2 (0.4%) | 1 (0.8%) | 4.06(0.23–72.03) | 0.34 | | 2 (0.4%) | 1 (0.5%) | 7.24(0.44–120) | 0.167 | |
| Log-addition | --- | --- | --- | 1.98(1.01–3.87) | 0.045* | 0.704 | --- | --- | 1.79(1.01–3.18) | 0.047* | 0.549 |
SNP: Single nucleotide polymorphism; OR: Odds ratio; 95% CI: 95% confidence interval; |
pa-value calculated by logistic regression analysis; |
pb-value calculated by logistic regression analysis with adjustments for gender, age, smoking, and drinking); |
*p-value < 0.05 indicates statistical significance. |
Stratified analysis based on clinical staging showed that "A/G" and "A/G-G/G" genotypes of rs1077868 were significantly correlated with lung cancer staging in codominant (OR = 1.96, 95% CI = 1.05–3.64, p = 0.034, power = 0.998) and dominant (OR = 2.03, 95% CI = 1.11–3.73, p = 0.022, power = 0.993) models, respectively. Rs1077868 was also significantly correlated with lung cancer staging in the additive model (OR = 1.92, 95% CI = 1.10–3.35, p = 0.021, power = 0.970) (Table 5).
Table 5
Stratified analysis of CMTM8 polymorphism and staging risk in patients with lung cancer
SNP | Model | Genotype | Control | Case | OR (95% CI) | p-value | Study power |
rs1077868 | Alleles | A | 147 (87.5%) | 423 (81.0%) | 1 | | |
| | G | 21 (12.5%) | 99 (19.0%) | 1.64 (0.99–2.72) | 0.054 | |
| Co-dominant | A/A | 64 (76.2%) | 170 (64.9%) | 1 | | |
| | A/G | 19 (22.6%) | 83 (31.7%) | 1.96(1.05–3.64) | 0.034* | 0.998 |
| | G/G | 1 (1.2%) | 8 (3.1%) | 3.28(0.39–27.22) | 0.272 | |
| Dominant | A/A | 64 (76.2%) | 170 (64.9%) | 1 | | |
| | A/G-G/G | 20 (23.8%) | 91 (34.8%) | 2.03(1.11–3.73) | 0.022* | 0.993 |
| Recessive | A/A-A/G | 83 (98.8%) | 253 (96.6%) | 1 | 0.348 | |
| | G/G | 1 (1.2%) | 8 (3.1%) | 2.69(0.33–22.16) | 0.358 | |
| Log-addition | --- | --- | --- | 1.92(1.10–3.35) | 0.021* | 0.970 |
ORs, odds ratios; CI, confidence interval; |
p-value calculated by logistic regression analysis with adjustments for gender and age, smoking, and drinking); |
*p value < 0.05 indicates statistical significance. |
Stratified subgroup in the case of lymph node metastasis, rs9835916 was found to be associated with lymph node metastasis risk in patients with lung cancer. For rs9835916, allele “C” increased the risk of lymphatic metastasis based on the allele model (OR = 1.56, 95% CI = 1.08–2.26, p = 0.018, power = 0.940), the "T/C" genotype increased the risk of lymphatic metastasis under the co-dominant model (OR = 2.49, 95% CI = 1.36–4.55, p = 0.003, power = 0.956), the "T/C-C/C" genotype was related to an increased lymphatic metastasis risk in the dominant model (OR = 2.40, 95% CI = 1.37–4.21, p = 0.002, power = 0.998). Rs9835916 also was significantly associated with an increased the risk of lymphatic metastasis based on the additive model (OR = 1.66, 95% CI = 1.11–2.48, p = 0.014, power = 0.978) (Table 6).
Table 6
Stratified analysis of the polymorphisms of CMTM8 and the risk of lymph node metastasis in patients with lung cancer
SNP | Model | Genotype | Control | Case | OR (95% CI) | p-value | Study power |
rs9835916 | Alleles | T | 103 (61.3%) | 293 (57.2%) | 1 | | |
| | C | 65 (38.7%) | 219 (42.8%) | 1.56 (1.08–2.26) | 0.018* | 0.940 |
| Co-dominant | T/T | 38 (45.2%) | 56 (26.3%) | 1 | | |
| | T/C | 33 (39.3%) | 119 (55.9%) | 2.49(1.36–4.55) | 0.003* | 0.956 |
| | C/C | 13 (15.5%) | 38 (17.8%) | 2.18(0.99–4.83) | 0.054 | |
| Dominant | T/T | 38 (45.2%) | 56 (26.3%) | 1 | | |
| | T/C-C/C | 46 (54.8%) | 157 (73.7%) | 2.40(1.37–4.21) | 0.002* | 0.998 |
| Recessive | T/T-C/T | 71 (84.5%) | 175 (82.2%) | 1 | | |
| | C/C | 13 (15.5%) | 38 (17.8%) | 1.3(0.63–2.69) | 0.473 | |
| Log-additive | --- | --- | --- | 1.66(1.11–2.48) | 0.014* | 0.978 |
ORs, odds ratios; CI, confidence interval; |
p-value calculated by logistic regression analysis with adjustments for gender and age, smoking, and drinking); |
*p value < 0.05 indicates statistical significance. |