肿瘤坏死因子基因组多态性在脓毒症发病中的作用

The associations of the single nucleotide polymorphisms on TNF and CD14 promoters with the mortality of infection, systematic inflammatory response syndromec and sepsis in surgical patients

目的 探讨肿瘤坏死因子 (TNF)及内毒素受体 (CD14 )基因组上单个核苷酸多态性(SNP)的频率、基因型与外科感染病人脓毒症发病的关系 ,观察SNP对在体单个核细胞 (PBMC)内TNF αmRNA表达的影响。方法 选择 113例外科感染的患者 ,10 0例正常人群为对照组 ,对TNF基因上 3个位点及CD14基因 1个位点进行PCR扩增、限制性内切酶酶切分析SNP基因型。患者分全身炎症反应综合征 (SIRS)组和脓毒症组 ,对各SNP基因型的频率进行分析。在出现脓毒症临床表现 2 4h内 ,对PBMC内TNF αmRNA表达水平进行测定。结果 TNF基因组上的 3个SNP均可影响在体PBMC内TNF αmRNA的表达。CD14基因组 - 15 9位点C→T、TNF基因组上 - 30 8位点G→A、- 86 3C→A 3个SNP与脓毒症的发生有相关性 (P <0 .0 5 )。结论 TNF基因组上的SNP通过影响TNF αmRNA的表达而影响机体对感染的反应性 ,产生SIRS甚至脓毒症等临床表现。

Objective To investigate the association of Single nucleotide polymorphism(SNPs) tumor necrosis factor (TNF) and CD14 promoter with the systematic inflammatory response syndromec(SIRS) and sepsis in surgical patients. Methods The DNA and RNA sample of PBMC from 113 patients, 40 of them being complicated with sepsis, and 100 healthy volunteers were extracted. The SNP genotypes of TNF-α -308 G/A, -863 C/A,CD14 -159C/T and TNFB1/B2 were examined by restriction fragment length polymorphism PCR (PCR-RFLP). The expressions of TNF-α mRNA of PBMC in parts of the patients who have at least one genotype of SNP were detected by RT-PCR. The risks for sepsis associated with polymorphisms in the TNF-α or CD14 promoter were determined by multivariate analysis. Results The rates of TNF2, -863A, CD14-159T alleles were 15%, 32.5%, and 40% respectively in patients with sepsis, significantly higher than those in the patients with SIRS (8.9%,22%, and 23.3%), and those in the healthy volunteers (5%, 16% and 26%). The expression of TNF-α mRNA was much higher in those patients with at least one kind of SNP than those without SNP. Conclusion The A-allele at the -308 and -863 position in the TNF-α promoter and the T-allele at the -159 position in the CD14 promoter increase the risk for sepsis. The effect of SNP genotypes on TNF-α expression can modulate inflammatory response.