Analysis of TRAF1/C5 and TNF-α gene polymorphisms with susceptibility to tuberculosis
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摘要:
目的 分析肿瘤坏死因子受体相关蛋白1(tumor necrosis factor receptor-associated factor 1, TRAF1)/补体5(complement component 5, C5) rs10818488和肿瘤坏死因子-α(tumor necrosis factor-alpha, TNF-α) rs1800629基因多态性、环境因素及其交互作用对结核病(tuberculosis, TB)易感性的影响。 方法 选取TB多发家庭中TB确诊患者作为TB病例组，当地社区同期体检的健康志愿者作为健康对照(healthy controls, HC)组，与TB组有血缘关系且共同居住者组成家庭密切接触(healthy household contacts, HHC)组。采用logistic回归分析模型分析基因型和环境因素与TB的关联，叉生分析结合logistic回归分析模型分析基因与环境交互作用。 结果 年龄＞45岁(χ2 =7.90, OR=2.28, 95%CI: 1.28~4.04, P=0.005)、吸烟(χ2 =15.27, OR=4.70, 95%CI: 2.16~10.22, P < 0.001)增加HHC组TB发病风险。吸烟(χ2 =13.94, OR=3.58, 95%CI: 1.83~7.01, P < 0.001)、居住地为农村(χ2 =25.05, OR=3.81, 95%CI: 2.26~6.42, P<0.001)和居室环境卫生较差(χ2 =15.31, OR=3.20, 95%CI: 1.79~5.73, P < 0.001)增加HC组TB发病风险。TRAF1/C5 rs10818488位点中，携带AG基因型(共显性及超显性模型)、GG基因型(共显性模型)和AG-GG基因型(显性模型)增加HHC组和HC组患TB风险。TNF-α rs1800629位点与TB易感性暂未显示存在关联。基因与环境交互作用分析显示，在TB组和HHC组间，TRAF1/C5 rs10818488位点AG-GG基因型与吸烟存在协同作用；而在TB组和HC组间，rs10818488位点AG-GG基因型与吸烟和居室环境卫生较差存在协同作用，与居住地存在相乘交互作用，均提高TB发病风险。 结论 TRAF1/C5 rs10818488位点的基因多态性可能与TB发病风险升高有关，且其与吸烟、居住地、居室环境卫生存在交互作用，共同影响TB的易感性。 -
关键词:
- 肿瘤坏死因子受体相关蛋白1 /
- 补体5 /
- 肿瘤坏死因子-α /
- 基因多态性 /
- 结核病
Abstract:Objective To analyze the effects of tumor necrosis factor receptor-associated factor 1 (TRAF1)/complement component 5 (C5) rs10818488 and tumor necrosis factor-alpha TNF-α rs1800629 gene polymorphisms, environmental factors, and their interactions on susceptibility to tuberculosis (TB). Methods The TB-confirmed patients in TB-prone families were selected as the case (TB) group. And the healthy volunteers who had medical checkups in the local community during the same period of time were selected as the healthy controls (HC) group. Besides and those who were related to the TB group and lived together were selected as the healthy household contacts (HHC) group. The association of genotype and environmental factors with TB was analyzed by a logistic regression analysis model, and the interaction between genes and environment was analyzed by crossover analysis combined with a logistic regression analysis model. Results Age above 45 years (χ2 =7.90, OR=2.28, 95%CI: 1.28-4.04, P=0.005), smoking (χ2 =15.27, OR=4.70, 95%CI: 2.16-10.22, P < 0.001) increased the risk of TB prevalence in the HHC group. Smoking (χ2 =13.94, OR=3.58, 95%CI: 1.83-7.01, P < 0.001), living in rural areas (χ2 =25.05, OR=3.81, 95%CI: 2.26-6.42, P < 0.001), and poor living room sanitation (χ2 =15.31, OR=3.20, 95%CI: 1.79-5.73, P < 0.001) increased the risk of TB prevalence in the HC group. Carriage of TRAF1/C5 rs10818488 AG genotype (co-dominant and hyper-dominant models), GG genotype (co-dominant model), and AG-GG genotype (dominant model) increased the risk of developing TB in the HHC and HC groups. No association between the TNF-α rs1800629 locus and TB susceptibility was found for the time being. Analyzing gene-environment interactions, there was a synergistic effect of the AG-GG genotype at the TRAF1/C5 rs10818488 locus with smoking between the TB and HHC groups, whereas there was a synergistic effect of the AG-GG genotype at the rs10818488 locus with smoking and poor living room sanitation, and a multiplicative interaction with the place of residence between the TB and HC groups, both of which increased the risk of TB prevelance. Conclusions Gene polymorphisms at the TRAF1/C5 rs10818488 locus may be associated with the risk of TB and interact with smoking, place of residence, and indoor sanitation to jointly influence susceptibility to TB. -
表 1 TB发病影响因素的单因素分析
Table 1. Univariate analysis of influencing factors of TB
变量 Variables TB组
group ①HHC组
group ①HC组
group ①TB组group∶ HHC组group TB组group∶ HC组group χ2值
valueP值
valueχ2值
valueP值
value年龄/岁 Age/years 9.85 0.002 0.99 0.318 < 45 60(45.1) 70(65.4) 88(50.9) ≥45 73(54.9) 37(34.6) 85(49.1) 性别 Gender 14.56 < 0.001 19.91 < 0.001 男性 Male 91(68.4) 47(43.9) 74(42.8) 女性 Female 42(31.6) 60(56.1) 99(57.2) 吸烟 Smoking 32.89 < 0.001 32.10 < 0.001 否 No 66(49.6) 91(85.0) 139(80.3) 是 Yes 67(50.4) 16(15.0) 34(19.7) 饮酒 Alcohol 1.35 0.245 2.48 0.116 否 No 93(69.9) 82(76.6) 106(61.3) 是 Yes 40(30.1) 25(23.4) 67(38.7) 居住地 Residence 0.02 0.902 35.17 < 0.001 农村 Rural 81(60.9) 66(61.7) 47(27.2) 城镇 Urban 52(39.1) 41(38.3) 126(72.8) 居室通风 Ventilation of living room 1.62 0.203 0.01 0.932 经常 Frequently 115(86.5) 86(80.4) 149(86.1) 不常 Infrequently 18(13.5) 21(19.6) 24(13.9) 居室环境卫生 Living room sanitation 1.22 0.269 20.43 < 0.001 良好 Good 79(59.4) 71(66.4) 143(82.7) 较差 Poor 54(40.6) 36(33.6) 30(17.3) 工作环境粉尘暴露 Workplace dust exposure 0.34 0.562 0.30 0.586 有 Yes 86(64.7) 73(68.2) 117(67.6) 无 No 47(35.3) 34(31.8) 56(32.4) 注：TB, 结核病; HHC, 家庭密切接触; HC, 健康对照。
①以人数(占比/%)表示。
Note: TB, tuberculosis; HHC, healthy household contacts; HC, healthy controls.
①Number of people(proportion/%).
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表 2 TB发病影响因素的多因素分析
Table 2. Multivariate analysis of influencing factors of TB
变量
Variablesβ值value sx Wald χ2值value OR值value (95% CI) P值value TB组group∶HHC组group 年龄/岁 Age/years < 45 1.00 ≥45 0.82 0.29 7.90 2.28(1.28~4.04) 0.005 性别 Gender 女性 Female 1.00 男性 Male 0.28 0.35 0.61 1.32(0.66~2.62) 0.434 吸烟 Smoking 否 No 1.00 是 Yes 1.55 0.40 15.27 4.70(2.16~10.22) < 0.001 TB组group∶HC组group 性别 Gender 女性 Female 1.00 男性 Male 0.23 0.32 0.50 1.26(0.67~2.37) 0.482 吸烟 Smoking 否 No 1.00 是 Yes 1.28 0.34 13.94 3.58(1.83~7.01) < 0.001 居住地 Residence 城镇 Urban 1.00 农村 Rural 1.34 0.27 25.05 3.81(2.26~6.42) < 0.001 TB组group∶HC组group 居室环境卫生 Living room sanitation 良好 Good 1.00 较差 Poor 1.16 0.30 15.31 3.20(1.79~5.73) < 0.001 注：TB，结核病；HHC，家庭密切接触；HC，健康对照。
Note: TB, tuberculosis; HHC, healthy household contacts; HC, healthy controls.
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表 3 两位点的基因型与等位基因在各组的分布情况
Table 3. The genotype and allele distribution of two loci in each group
位点
Locus基因型/等位基因
Genotypes/AlleleTB组
group ①
(n=133)HHC组
group ①
(n=107)HC组
group ①
(n=173)TB组group∶HHC组group TB组group∶HC组group χ2值
valueP值
valueχ2值
valueP值
valueTRAF1/C5 rs10818488 AA 32(24.1) 50(46.7) 82(47.4) 13.60 0.001 19.32 < 0.001 AG 69(51.9) 40(37.4) 70(40.5) GG 32(24.1) 17(15.9) 21(12.1) A 133(50.0) 140(65.4) 234(67.6) 11.50 0.001 19.47 < 0.001 G 133(50.0) 74(34.6) 112(32.4) TNF-α rs1800629 AA 2(1.5) 1(0.9) 1(0.6) 1.40 0.496 1.89 0.388 AG 21(15.8) 23(21.5) 20(11.6) GG 110(82.7) 83(77.6) 152(87.8) A 25(9.4) 25(11.7) 57(16.5) 0.66 0.416 6.49 0.011 G 241(90.6) 189(88.3) 289(83.5) 注：TB, 结核病; HHC, 家庭密切接触; HC, 健康对照。
①以人数(占比/%)表示。
Note: TB, tuberculosis; HHC, healthy household contacts; HC, healthy controls.
① Number of people(proportion/%).
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表 4 两位点遗传模型与TB的关联性分析
Table 4. Association analysis of two locus genetic model and TB
位点
Locus遗传模型
Genetic model基因型/等位基因
Genotypes/AlleleTB组
group ①
(n=133)HHC组
group ①
(n=107)HC组
group ①
(n=173)TB组group∶HHC组group TB组group∶HC组group OR值value
(95% CI)P值
valueOR值value
(95% CI)P值value TRAF1/C5 rs10818488 共显性 Co-dominant AA 32(24.1) 50(46.7) 82(47.4) 1.00 1.00 AG 69(51.8) 40(37.4) 70(40.5) 2.94(1.52~5.66) 0.001 3.17(1.71~5.87) < 0.001 GG 32(24.1) 17(15.9) 21(12.1) 3.55(1.57~8.03) 0.002 4.50(2.03~9.95) < 0.001 显性 Dominant AA 32(24.1) 50(46.7) 82(47.4) 1.00 1.00 AG-GG 101(75.9) 57(53.3) 91(52.6) 3.11(1.69~5.75) < 0.001 3.49(1.95~6.25) < 0.001 隐性 Recessive AA-AG 101(75.9) 90(84.1) 152(87.9) 1.00 1.00 GG 32(24.1) 17(15.9) 21(12.1) 1.92(0.94~3.92) 0.073 2.33(1.16~4.65) 0.016 超显性 Hyper-dominant AA-GG 64(48.1) 67(62.6) 103(59.5) 1.00 1.00 AG 69(51.9) 40(37.4) 70(40.5) 1.83(1.04~3.24) 0.037 1.89(1.11~3.22) 0.018 TNF-α rs1800629 共显性 Co-dominant GG 110(82.7) 83(77.6) 152(87.9) 1.00 1.00 AG 21(15.8) 23(21.5) 20(11.6) 0.74(0.36~1.53) 0.411 1.55(0.69~3.47) 0.286 AA 2(1.5) 1(0.9) 1(0.5) 0.75(0.06~9.65) 0.822 3.59(0.24~53.87) 0.355 显性 Dominant GG 110(82.7) 83(77.6) 152(87.9) 1.00 1.00 AG-AA 23(17.3) 24(22.4) 21(12.1) 0.74(0.36~1.50) 0.400 1.65(0.76~3.59) 0.207 隐性 Recessive GG-AG 131(98.5) 106(99.1) 172(99.4) 1.00 1.00 AA 2(1.5) 1(0.9) 1(0.6) 0.79(0.06~10.14) 0.853 3.38(0.23~50.63) 0.377 超显性 Hyper-dominant GG-AA 112(84.2) 84(78.5) 153(88.4) 1.00 1.00 AG 21(15.8) 23(21.5) 20(11.6) 0.74(0.36~1.53) 0.417 1.52(0.68~3.40) 0.305 注：TB, 结核病; HHC, 家庭密切接触; HC, 健康对照。
①以人数(占比/%)表示。
Note: TB, tuberculosis; HHC, healthy household contacts; HC, healthy controls.
① Number of people(proportion/%).
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表 5 rs10818488位点AG-GG基因型与环境因素相乘交互作用
Table 5. Multiplicative interaction of the AG-GG genotype at locus rs10818488 with environmental factors
组别
Groups交互因素
Interacting factorsβ值
valueWald χ2值
valueOR值value
(95% CI)P值
valueTB组group∶HHC组group AG-GG*年龄AG-GG*Age 0.96 2.26 2.61(0.75~9.09) 0.133 AG-GG*吸烟AG-GG*Smoking 0.21 0.09 1.23(0.32~4.78) 0.762 TB组group∶HC组group AG-GG*吸烟AG-GG*Smoking 0.15 0.06 1.16(0.35~3.82) 0.807 AG-GG*居住地AG-GG*Residence 1.83 7.80 6.22(1.72~22.46) 0.005 AG-GG*居室环境卫生AG-GG*Living room sanitation 1.22 3.44 3.39(0.93~12.31) 0.063 注：TB，结核病；HHC，家庭密切接触；HC，健康对照。
Note: TB, tuberculosis; HHC, healthy household contacts; HC, healthy controls.
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表 6 叉生分析基因与环境的交互作用
Table 6. Crossover analysis of gene-environment interactions
组别
Groups危险因素
Risk factors基因
Genes环境
Environment病例/对照
Cases/ControlsOR值value
(95% CI)P值
valueRERI值value
(95% CI)S值value
(95% CI)TB组 group∶
HHC组 groupTRAF1/C5 rs10818488 *年龄
TRAF1/C5 rs10818488 *Age- - 12/34 1.00 -0.16(-23.62~23.30) 0.98(0.04~27.43) + - 48/36 4.90(2.04~11.75) < 0.001 - + 20/16 4.26(1.53~11.83) 0.005 + + 53/21 8.00(3.21~19.91) < 0.001 TRAF1/C5 rs10818488 *吸烟
TRAF1/C5 rs10818488 *Smoking- - 15/41 1.00 12.05(-34.81~58.92) 2.92(0.12~68.93) + - 51/50 2.93(1.42~6.04) 0.004 - + 17/9 5.35(1.93~14.86) 0.001 + + 50/7 19.34(7.11~52.62) < 0.001 TB组 group∶
HC组 groupTRAF1/C5 rs10818488 *吸烟
TRAF1/C5 rs10818488 *Smoking- - 15/64 1.00 8.77(-27.56~45.10) 2.68(0.11~64.19) + - 51/75 3.31(1.61~6.83) 0.001 - + 17/18 3.90(1.51~10.10) 0.005 + + 50/16 14.98(6.33~35.47) < 0.001 TRAF1/C5 rs10818488 *居住地
TRAF1/C5 rs10818488 *Residence- - 6/61 1.00 -0.75(-66.82~65.33) 0.97(0.05~19.93) + - 46/65 9.39(3.49~25.21) < 0.001 - + 26/21 15.01(5.00~45.08) < 0.001 + + 55/26 22.65(8.13~63.08) < 0.001 TRAF1/C5 rs10818488 *居室环境卫生
TRAF1/C5 rs10818488 *Living room sanitation- - 21/64 1.00 9.95(-18.69~38.59) 5.91(0.19~183.18) + - 58/79 2.49(1.28~4.85) 0.007 - + 11/18 1.54(0.56~4.24) 0.404 + + 43/12 12.98(5.33~31.62) < 0.001 注：TB，结核病；HHC，家庭密切接触；HC，健康对照；RERI，超额相对危险度；S，交互作用指数；TRAF1/C5 rs10818488(+)表示基因型AG-GG，TRAF1/C5 rs10818488(-)表示基因型AA；年龄(+)表示≥45岁，年龄(-)表示 < 45岁；吸烟(+)表示吸烟，吸烟(-)表示不吸烟；居住地(+)表示农村，居住地(-)表示城镇；居室环境卫生(+)表示较差，居室环境卫生(-)表示良好。
Note: TB, tuberculosis; HHC, healthy household contacts; HC, healthy controls; RERI, relativeexcess risk of interaction; S, the synergyindex; TRAF1/C5 rs10818488 (+) indicates genotype AG-GG and TRAF1/C5 rs10818488 (-) indicates genotype AA; age (+) indicates age greater than or equal to 45 years and age (-) indicates age less than 45 years; smoking (+) indicates smoking and smoking (-) indicates non-smoking; place of residence (+) indicates rural residence and place of residence (-) indicates urban residence; Living room sanitation (+) indicates poor, Living room sanitation (-) indicates good.
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