目的 探讨肿瘤坏死因子-α(TNF-α)单核苷酸多态性(SNP)与非酒精性脂肪性肝病(NAFLD)发病及病程进展的相关性.方法 在2005年对普通人群NAFLD流行病学调查的基础上进行队列追踪到2009年(中位数4年),其中696例愿意接受复查,每例再行问卷、体检、血生化和B超检查,应用PCR-RFLP方法检测TNF-α 3个位点:-238、-308和-857的SNP.结果 2005年NAFLD标化患病率为21.29%,至2009年显著升高达46.11%.Hardy-Weinberg检验-238位点基因频率未达到遗传平衡(P<0.05),故予剔除,而-308及-857位点纳入研究.NAFLD患者与正常对照者比较,TNF-α -857位点的基因型及等位基因频率差异均有统计学意义(P<0.05),等位基因T型者的发病危险率(RR)是正常对照者的1.463倍;而-308位点两者差异无统计学意义(P＞0.05).有序logistic回归分析显示,性别对病程无显著影响(P＞0.05),年龄影响显著(P<0.001);校正性别和年龄后,-857位点T/T基因型与病程进展呈正相关,其危险性(OR)是C/C型的8.65倍(P<0.001),而C/T型与C/C型比较差异无统计学意义(P=0.072);-308位点各基因型对病程均无显著影响(P＞0.05).结论 TNF-α -857位点C→T变异(而非-308位点)与NAFLD发病易感性及病程进展两者均呈正相关,T/T型增加疾病发生和进展的风险.%Objective To investigate the correlation between the tumor necrosis factor-alpha ( TNF-α ) single nucleotide polymorphism ( SNP ) and the pathogenesis of non-alcoholic fatty liver diseases ( NAFLD ). Methods Base on our previous population-based epidemiological survey in 2005 ( baseline ), the follow-up was performed ( medium, 4 years; to 2009 ). Questionnaires, physical examination, blood test and abdominal BUG were carried out on 696 consensus subjects. PCR - RFLP was applied to assess the SNP at loci -238, -203, and - 857 of TNF-α. Results The standard prevalence of NAFLD was significantly increased from 21. 29% in 2005 to 46. 11% in 2009. The SNP distribution at the -238 locus was excluded due to the failure of Hardy - Weinberg equilibrium test. There were significant differences in both genotype and allele frequencies at - 857 locus between the NAFLD group and normal control ( P < 0. 05 ), with the relative risk ( RR ) of T allele to control of 1. 463. However, there was no significant difference found in genotype or allele frequencies at -308 locus between the two groups ( P >0. 05 ). Ordinal logistic regression analysis showed that gender did not influence NAFLD progression ( P > 0. 05 ), but age did significantly ( P <0. 001 ). After age and gender adjusted , T/T genotype at-857 locus was significantly positively correlated with the NAFLD progression, with the odd ratio ( OR ) of 8. 65 when comparing with the C/C genotype ( P < 0. 001 ), while there was significant difference between the C/T and the C/C genotypes ( P =0. 072 ). Furthermore, there was no significant impact of the genotype at -308 locus on NAFLD progression. Conclusion TNF-α.-857 C→T variation ( but not-308 site ) is positively correlated to both occurrence and progression of NAFLD. The T/T genotype is the independent risk factor for NAFLD.
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