肿瘤坏死因子基因多态性与阻塞性睡眠呼吸暂停低通气综合征

The relationship between tumor necrosis factor-α gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome

目的探讨肿瘤坏死因子α(TNF-α)启动子上游308位点(TNF-αG-308A)多态性与阻塞性睡眠呼吸暂停低通气综合征(OSAHS)的关系。方法研究对象为2004年6月至2005年12月我院睡眠检测中心就诊的患者。采用酶联免疫吸附测定(ELISA)法测定76例 OSAHS 组和42例非OSAHS 对照组血清中 TNF-α水平,并对76例中的18例患者进行持续气道正压通气(CPAP)治疗,测定治疗1个月后患者血清中 TNF-α水平;采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,检测76例患者 TNF-αG-308A 基因多态性频率及分布,分析该基因多态性与体重指数(BMI)、颈围、腰臀比、多导睡眠图监测(PSG)相关参数以及收缩压、舒张压等的关系。结果 OSAHS 组 TNF-α的血清水平[(12.32±3.62)ng/L]较对照组[(8.59±1.62)ng/L]明显增高(t=7.716,P<0.01);18例患者进行 CPAP 治疗1个月后血清中 TNF-α水平下降为(10.31±1.91)ng/L,但仍未恢复至正常水平;OSAHS 组 AA/AG 基因型频率(31/76,41%)显著高于对照组(7/42,17%;X^2=7.485,P<0.05),其 A 等位基因频率(39/152,25.7%)高于对照组(39/152,9.5%),差异有统计学意义(X^2=8.830,P<0.01)。OSAHS 组 AA/AG 基因型患者血清中 TNF-α水平、颈围、腰臀比、呼吸暂停低通气指数(AHI)[分别为(13.39±3.71)ng/L、(45.2±4.2)cm、(0.91±0.12)和(34.8±15.6)次/h]均高于 GG 基因型[分别为(11.09±3.54)ng/L、(42.7±4.9)cm、(0.85±0.12)和(26.4±12.3)次/h],而最低血氧饱和度(LSaO_2)前者低于后者[(78.8±10.9)%,(83.4±8.6)%],差异均有统计学意义(t 值分别为2.725,2.278,2.150,2.609,2.039;P<0.05或<0.01);BMI、收缩压、舒张压比较差异无统计学意义。结论 OSAHS 的发病与 TNF-αG-308A 基因多态性相关,该基因多态性可能在一定程度上增加了 OSAHS 的遗传易感性。

Objective To investigate the relationship between tumor necrosis factor-α （TNF-α） gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome （OSAHS）. Methods The plasma TNF-α level of OSAHS group and non-OSAHS group was detected by enzyme-linked immunosorbent assay （ELISA）. Eighteen patients with severe OSAHS were treated with continuous positive airway pressure （CPAP） for 1 month, and the serum levels of TNF-α was also measured. The genotypes of TNF-α gene promoter polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphisms（ PCR-RFLP ）. The genotypes and allele of the polymorphisms were compared between OSAHS group and non-OSAHS group. The effects of the polymorphisms in OSAHS group on body mass index （ BMI） , neck circumference （ NC ） , waist/hip rate （ WHR ） , polysomnography （ PSG ） , systolic blood pressure （SBP）,diastolic blood pressure（DBP） were analyzed. Results The plasma level of TNF-α in OSAHS group was higher than the control group [ （12. 3 ±3.62） ng/L and （8.59 ± 1.62） ng/L,respectively, t = 7. 716 ,P 〈 0. 01 ]. CPAP significantly decreased the serum levels of TNF-α, but its level （ 10. 31 ± 1.91 ） ng/L was still higher in the patients than the control group. The frequencies of TNF-α AA/AG genotype in OSAHS group（ frequencies 31/76, 40. 8% ） was higher than the control one （ frequencies 7/42,16. 7% ） （χ^2 =7. 485 ,P 〈0. 05 ）. Statistical analysis showed that OSAHS group had a significantly higher TNF-αA allele frequency （ frequencies 39/152,25.7% ） than that of the control one （ frequencies 39/152,9. 5% ）（ χ^2 = 8. 830, P 〈 0. 01 ）. The OSAHS patients with AA/AG genotype had significantly higher serum levels of TNF-α,NC ,WHR and aphea-hypopnea index [ （ 13.39 ± 3.71 ） ng/L, （45.2 ±4. 2） cm, （0. 91 ±0. 12）, and （34. 8 ± 15. 6）/h , respectively ] than those with GG genotype group[ （ 11.09 ± 3. 54） ng/L, （42. 7 ± 4.9） cm, （0.85 ±0.12） and （26.4 ± 12.3）/h, respectively] （ t = 2.725,2.278,2. 150,2.609 respectively, P 〈 0. 05 or 〈 0.01 ）. The L SaO2 （ the lowest SaO2 ） in patients with AA/AG genotype [ （78. 8 ± 10. 9）% ] was significantly lower than that in patients with GG genotype [ （83.4 ± 8.6）% ] （t = 2. 039, P 〈 0. 05 ）. There was no significant difference in BMI, SBP and DBP. Conclusion The presence of the TNF-αA allele may be associated with susceptibility to OSAHS, and it maybe an important candidate gene for OSAHS.