Interaction between genetic variation and Helicobacter pylori infection in the occurrence of gastric cancer
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摘要:
目的 探讨胃癌已知易感遗传变异与幽门螺杆菌(Helicobacter pylori, H. pylori)在胃癌发生中的交互作用，及其对胃癌发生部位和发病年龄的影响。 方法 采用单纯病例研究设计，在2 426例胃癌患者中，通过二元Logistic回归分析模型分析遗传变异与H. pylori之间的交互作用。 结果 调整混杂因素后发现，遗传变异NSUN 3 rs7624041和DEFB rs2376549与H. pylori感染在胃癌发生中交互作用有统计学意义(OR=1.257，95% CI：1.006~1.571，P=0.044；OR=0.845，95% CI：0.715~0.999，P=0.048)。基于肿瘤部位的分层分析发现，遗传变异与H. pylori感染之间不存在交互作用。基于肿瘤TNM(tumor-node-metastasis)分期的分层分析发现，在TNM早期胃癌患者中，遗传变异lnc-POLR3G-4 rs7712641与H. pylori感染交互作用有统计学意义(OR=1.757，95% CI：1.060~2.915，P=0.029)。基于年龄的分层分析发现，在年龄 < 60岁人群中，ASHIL rs80142782、NSUN 3 rs7624041和DEFB rs2376549与H. pylori感染交互作用有统计学意义(OR=1.602，95% CI：1.006~2.551，P=0.047；OR=1.811，95% CI：1.247~2.632，P=0.002；OR=0.688，95% CI：0.520~0.910，P=0.009)；而在年龄≥60岁人群中，仅有PSCA rs2294008和CUX 2 rs6490061与H. pylori感染交互作用有统计学意义(OR=0.775，95% CI：0.630~0.954，P=0.016；OR=0.790，95% CI：0.635~0.982，P=0.034)。 结论 胃癌的发生发展较为复杂，通过整合遗传因素和环境因素，针对易感高危人群采取H. pylori的根除措施，将有助于预防胃癌的发生发展。 Abstract:Objective To investigate the interaction between known genetic variation of gastric cancer and Helicobacter pylori (H. pylori) in the occurrence of gastric cancer, and its effect on tumor site and the age at onset of gastric cancer. Methods With a case-only design, the interaction between genetic variation and H. pylori was analyzed by binary Logistic regression analysis in 2 426 patients with gastric cancer. Results After adjusting confounding factors, the interactions of genetic variation NSUN 3 rs7624041 and DEFB rs 2376549 with H. pylori infection in gastric cancer were statistically significant (OR=1.257, 95% CI: 1.006-1.571, P=0.044; OR=0.845, 95% CI: 0.715-0.999, P=0.048). Based on the hierarchical analysis of tumor location, there was no interaction between genetic variation and H. pylori infection. Hierarchical analysis based on tumor stage showed that the interaction between lnc-POLR3G-4 rs7712641 and H. pylori infection was statistically significant in patient with early gastric cancer (OR=1.757, 95% CI: 1.060-2.915, P=0.029). The age-based stratified analysis results showed that the interactions between ASHIL rs80142782, NSUN 3 rs7624041, DEFB rs2376549 and H. pylori infection were statistically significant in people aged < 60 years (OR=1.602, 95% CI: 1.006-2.551, P=0.047; OR=1.811, 95% CI: 1.247-2.632, P=0.002; OR=0.688, 95% CI: 0.520-0.910, P=0.009). And the interactions between PSCA rs2294008, CUX 2 rs6490061 and H. pylori infection were statistically significant in people over 60 years old (OR=0.775, 95% CI: 0.630-0.954, P=0.016; OR=0.790, 95% CI: 0.635-0.982, P=0.034). Conclusions The occurrence and development of gastric cancer is complex. It is helpful to prevent the occurrence and development of gastric cancer by integrating genetic factors and environmental factors and taking targeted H. pylori eradication measures for susceptible and high-risk groups. -
Key words:
- Gastric cancer /
- Genetic variation /
- Helicobacter pylori /
- Case-only study /
- Interaction
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表 1 研究对象基本信息[n(%)]
Table 1. Baseline information of participants [n(%)]
变量 例数 H. pylori阳性(n=1 344) H. pylori阴性(n=1 082) χ2值 性别 1.745 男 1 814 1 019(75.8) 795(73.5) 女 612 325(24.2) 287(26.5) 吸烟 3.224 是 807 472(36.8) 335(33.2) 否 1 482 809(63.2) 673(66.8) 饮酒 1.630 是 680 395(30.9) 285(28.4) 否 1 600 883(69.1) 717(71.6) 肿瘤部位 0.663 非贲门 1 009 570(60.3) 439(58.3) 贲门 690 376(39.7) 314(41.7) TNM分期 4.823 早期 347 202(39.8) 145(32.9) 晚期 602 306(60.2) 296(67.1) 
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表 2 遗传变异与H. pylori的交互作用[n(%)]
Table 2. Interaction between genetic variation and H. pylori [n(%)]
染色体及遗传变异 H. pylori阳性(n=1 344) H. pylori阴性(n=1 082) OR(95% CI)值 a P值 染色体及遗传变异 H. pylori阳性(n=1 344) H. pylori阴性(n=1 082) OR(95% CI)值a P值 1q22 6p22.1 MUCI rs4072037 BTN 3A 2 rs 1679709 CT+CC 330(24.6) 290(26.8) 1.000 AG+AA 354(26.3) 305(28.2) 1.000 TT 1014(75.4) 792(73.2) 1.123(0.929~1.358) 0.229 GG 990(73.7) 777(71.8) 1.096(0.910~1.321) 0.334 1q22 6p21.1 ASHIL rs 80142782 UNC 5CL, TSPO 2 rs 2294693 CT+CC 145(10.8) 135(12.5) 1.000 TT 800(59.5) 613(56.7) 1.000 TT 1 199(89.2) 947(87.5) 1.213(0.938~1.568) 0.141 CT+CC 544(40.5) 469(43.3) 0.912(0.770~1.079) 0.282 3q11.2 8q24.3 NSUN 3 rs7624041 PSCA rs2294008 AA 1 096(81.5) 911(84.2) 1.000 CC 677(50.4) 516(47.7) 1.000 AG+GG 248(18.5) 171(15.8) 1.257(1.006~1.571) 0.044 CT+TT 667(49.6) 566(52.3) 0.875(0.741~1.033) 0.115 3q13.31 9q34.2 ZBTB20 rs9841504 ABO rs7849280 CG+GG 338(25.1) 265(24.5) 1.000 AG+GG 550(40.9) 459(42.4) 1.000 CC 1 006(74.9) 817(75.5) 1.023(0.844~1.242) 0.814 AA 794(59.1) 623(57.6) 1.084(0.916~1.283) 0.347 4q28.1 10q23.33 LOC285419, ANKRD50 rs 10029005 PLCE 1, KIAA 1516 rs 2274223 GG 571(42.5) 436(40.3) 1.000 AA 720(53.6) 545(50.4) 1.000 AG+AA 773(57.5) 646(59.7) 0.913(0.772~1.081) 0.293 AG+GG 624(46.4) 537(49.6) 0.928(0.786~1.096) 0.380 5p13.1 12q24.11-12 PRKAA 1 rs 1 3361707 CUX 2 rs6490061 TT 281(20.9) 239(22.1) 1.000 CC 525(39.1) 415(38.4) 1.000 CT+CC 1 063(79.1) 843(77.9) 1.083(0.886~1.325) 0.437 CT+TT 819(60.9) 667(61.6) 0.954(0.804~1.132) 0.592 5q14.3 20q11.21 lnc-POLR3G-4 rs7712641 DEFB家族rs2376549 CT+TT 950(70.7) 773(71.4) 1.000 TT 773(57.5) 578(53.4) 1.000 CC 394(29.3) 309(28.6) 1.021(0.851~1.226) 0.821 CT+CC 571(42.5) 504(46.6) 0.845(0.715~0.999) 0.048 注：a调整年龄、性别、吸烟以及饮酒。
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表 3 不同TNM分期中遗传变异与H. pylori对胃癌发生的交互作用[n(%)]
Table 3. Interaction between genetic variation and H. pylori infection in different TNM stages of gastric cancer [n(%)]
染色体及遗传变异 TNM早期(N=347) TNM晚期(N=602) H. pylori阳性(n=202) H. pylori阴性(n=145) OR(95% CI)值 a P值 H. pylori阳性(n=306) H. pylori阴性(n=296) OR(95% CI)值 a P值 1q22 MUCI rs4072037 CT+CC 46(22.8) 39(26.9) 1.000 75(24.5) 68(23.0) 1.000 TT 156(77.2) 106(73.1) 1.331(0.797~2.224) 0.275 231(75.5) 228(77.0) 0.834(0.563~1.237) 0.367 1q22 ASHIL rs80142782 CT+CC 23(11.4) 17(11.7) 1.000 30(9.8) 38(12.8) 1.000 TT 179(88.6) 128(88.3) 1.128(0.569~2.234) 0.731 276(90.2) 258(87.2) 1.254(0.735~2.142) 0.406 3q11.2 NSUN 3 rs7624041 AA 166(82.2) 128(88.3) 1.000 254(83.0) 248(83.8) 1.000 AG+GG 36(17.8) 17(11.7) 1.539(0.796~2.974) 0.200 52(17.0) 48(16.2) 1.104(0.707~1.723) 0.664 3q13.31 ZBTB 20 rs9841504 CG+GG 55(27.2) 34(23.4) 1.000 85(27.8) 76(25.7) 1.000 CC 147(72.8) 111(76.6) 0.847(0.507~1.415) 0.527 221(72.2) 220(74.3) 1.005(0.690~1.466) 0.978 4q28.1 LOC 285419, ANKRD 50 rs10029005 GG 90(44.6) 54(37.2) 1.000 136(44.4) 122(41.2) 1.000 AG+AA 112(55.4) 91(62.8) 0.742(0.470~1.172) 0.201 170(55.6) 174(58.8) 0.882(0.630~1.233) 0.462 5p13.1 PRKAA 1 rs13361707 TT 43(21.3) 28(19.3) 1.000 70(22.9) 65(22.0) 1.000 CT+CC 159(78.7) 117(80.7) 0.902(0.517~1.574) 0.716 236(77.1) 231(78.0) 0.922(0.619~1.371) 0.687 5q14.3 lnc-POLR3G-4 rs7712641 CT+TT 132(65.3) 112(77.2) 1.000 224(73.2) 222(75.0) 1.000 CC 70(34.7) 33(22.8) 1.757(1.060~2.915) 0.029 82(26.8) 74(25.0) 1.093(0.748~1.597) 0.647 6p22.1 BTN 3A 2 rs1679709 AG+AA 50(24.8) 37(25.5) 1.000 94(30.7) 79(26.7) 1.000 GG 152(75.2) 108(74.5) 1.083(0.647~1.812) 0.762 212(69.3) 217(73.3) 0.840(0.583~1.209) 0.347 6p21.1 UNC 5CL, TSPO 2 rs2294693 TT 128(63.4) 89(61.4) 1.000 174(56.9) 163(55.1) 1.000 CT+CC 74(36.6) 56(38.6) 0.973(0.611~1.550) 0.909 132(43.1) 133(44.9) 0.998(0.715~1.392) 0.990 8q24.3 PSCA rs2294008 CC 102(50.5) 80(55.2) 1.000 156(51.0) 144(48.6) 1.000 CT+TT 100(49.5) 65(44.8) 1.147(0.732~1.795) 0.550 150(49.0) 152(51.4) 0.926(0.663~1.292) 0.650 9q34.2 ABO rs7849280 AG+GG 85(42.1) 63(43.4) 1.000 117(38.2) 124(41.9) 1.000 AA 117(57.9) 82(56.6) 1.097(0.698~1.723) 0.688 189(61.8) 172(58.1) 1.135(0.809~1.592) 0.464 10q23.33 PLCE 1, KIAA 1516 rs2274223 AA 109(54.0) 72(49.7) 1.000 168(54.9) 147(49.7) 1.000 AG+GG 93(46.0) 73(50.3) 0.853(0.543~1.340) 0.490 138(45.1) 149(50.3) 0.883(0.632~1.234) 0.466 12q24.11-12 CUX 2 rs6490061 CC 77(38.1) 72(49.7) 1.000 117(38.2) 118(39.9) 1.000 CT+TT 125(61.9) 73(50.3) 1.478(0.940~2.323) 0.090 189(61.8) 178(60.1) 1.061(0.754~1.492) 0.735 20q11.21 DEFB家族rs2376549 TT 117(57.9) 80(55.2) 1.000 161(52.6) 152(51.4) 1.000 CT+CC 85(42.1) 65(44.8) 1.005(0.640~1.578) 0.983 145(47.4) 144(48.6) 0.954(0.685~1.329) 0.780 注：a调整年龄、性别、吸烟以及饮酒。
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表 4 不同发病年龄中遗传变异与H. pylori对胃癌发生的交互作用[n(%)]
Table 4. Interaction between genetic variation and H. pylori infection in different age groups of gastric cancer [n(%)]
染色体及遗传变异 发病年龄 < 60岁(N=872) 发病年龄≥60岁(N=1 554) H. pylori阳性(n=485) H. pylori阴性(n=387) OR(95% CI)值 a P值 H. pylori阳性(n=859) H. pylori阴性(n=695) OR(95% CI)值 a P值 1q22 MUCI rs4072037 CT+CC 101(20.8) 101(26.1) 1.000 229(26.7) 189(27.2) 1.000 TT 384(79.2) 286(73.9) 1.291(0.930~1.793) 0.127 630(73.3) 506(72.8) 1.053(0.835~1.329) 0.662 1q22 ASHIL rs80142782 CT+CC 38(7.8) 47(12.1) 1.000 107(12.5) 88(12.7) 1.000 TT 447(92.2) 340(87.9) 1.602(1.006~2.551) 0.047 752(87.5) 607(87.3) 1.079(0.792~1.470) 0.630 3q11.2 NSUN 3 rs7624041 AA 379(78.1) 333(86.0) 1.000 717(83.5) 578(83.2) 1.000 AG+GG 106(21.9) 54(14.0) 1.811(1.247~2.632) 0.002 142(16.5) 117(16.8) 1.018(0.769~1.348) 0.901 3q13.31 ZBTB20 rs9841504 CG+GG 110(22.7) 85(22.0) 1.000 228(26.5) 180(25.9) 1.000 CC 375(77.3) 302(78.0) 0.988(0.704~1.388) 0.946 631(73.5) 515(74.1) 1.037(0.819~1.313) 0.762 4q28.1 LOC285419, ANKRD50 rs10029005 GG 213(43.9) 147(38.0) 1.000 358(41.7) 289(41.6) 1.000 AG+AA 272(56.1) 240(62.0) 0.774(0.582~1.029) 0.078 501(58.3) 406(58.4) 1.008(0.817~1.244) 0.939 5p13.1 PRKAA1 rs13361707 TT 98(20.2) 91(23.5) 1.000 183(21.3) 148(21.3) 1.000 CT+CC 387(79.8) 296(76.5) 1.230(0.879~1.722) 0.227 676(78.7) 547(78.7) 1.017(0.790~1.309) 0.895 5q14.3 lnc-POLR3G-4 rs7712641 CT+TT 337(69.5) 276(71.3) 1.000 613(71.4) 497(71.5) 1.000 CC 148(30.5) 111(28.7) 1.009(0.746~1.367) 0.952 246(28.6) 198(28.5) 1.035(0.823~1.301) 0.771 6p22.1 BTN 3A 2 rs1679709 AG+AA 121(24.9) 106(27.4) 1.000 233(27.1) 199(28.6) 1.000 GG 364(75.1) 281(72.6) 1.168(0.850~1.605) 0.338 626(72.9) 496(71.4) 1.055(0.837~1.329) 0.649 6p21.1 UNC 5CL, TSPO 2 rs2294693 TT 286(59.0) 220(56.8) 1.000 514(59.8) 393(56.5) 1.000 CT+CC 199(41.0) 167(43.2) 0.929(0.701~1.232) 0.611 345(40.2) 302(43.5) 0.902(0.730~1.113) 0.335 8q24.3 PSCA rs2294008 CC 216(44.5) 186(48.1) 1.000 461(53.7) 330(47.5) 1.000 CT+TT 269(55.5) 201(51.9) 1.098(0.831~1.450) 0.512 398(46.3) 365(52.5) 0.775(0.630~0.954) 0.016 9q34.2 ABO rs7849280 AG+GG 224(46.2) 171(44.2) 1.000 326(38.0) 288(41.4) 1.000 AA 261(53.8) 216(55.8) 0.936(0.708~1.238) 0.644 533(62.0) 407(58.6) 1.181(0.956~1.459) 0.123 10q23.33 PLCE 1, KIAA 1516 rs2274223 AA 259(53.4) 198(51.2) 1.000 461(53.7) 347(49.9) 1.000 AG+GG 226(46.6) 189(48.8) 0.954(0.722~1.261) 0.742 398(46.3) 348(50.1) 0.912(0.741~1.123) 0.386 12q24.11-12 CUX 2 rs6490061 CC 195(40.2) 178(46.0) 1.000 330(38.4) 237(34.1) 1.000 CT+TT 290(59.8) 209(54.0) 1.297(0.980~1.717) 0.069 529(61.6) 458(65.9) 0.790(0.635~0.982) 0.034 20q11.21 DEFB家族rs2376549 TT 281(57.9) 197(50.9) 1.000 492(57.3) 381(54.8) 1.000 CT+CC 204(42.1) 190(49.1) 0.688(0.520~0.910) 0.009 367(42.7) 314(45.2) 0.954(0.774~1.176) 0.660 注：a调整年龄、性别、吸烟以及饮酒。
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