肿瘤坏死因子-α基因多态性对非酒精性脂肪性肝病发病和病程进展的影响

The roles of tumor necrosis factor-α gene polymorphisms in the pathogenesis of non-alcoholic fatty liver diseases

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-α3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 stand- ard 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 adjus- ted, 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 〈 O. 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.