TNFSF15基因多态性及其相关蛋白与原发性胆汁性胆管炎的相关性

Correlation between TNFSF15 gene polymorphism and its related protein and primary biliary cholangitis

目的探讨肿瘤坏死因子15(TNFSF15)基因单核苷酸多态性(SNP)及其相关蛋白肿瘤坏死因子样配体1A(TL1A)与原发性胆汁性胆管炎(PBC)发病的关系,并分析关联阳性的SNP位点基因分型与其生化指标的相关性,为诊断PBC高危人群及发现新的治疗靶点提供新的线索。方法选取2018年9月至2020年9月贵州省人民医院120例PBC患者为病例组,选取同期受检于本院的120名健康体检者为对照组。筛选目标SNP位点rs55717217、rs6478108、rs4979462、rs10114470、rs1857335、rs12235514。应用Sanger测序对研究人群的目标SNP位点进行基因分型。检测两组外周血TL1A的浓度并分析其及SNP位点不同等位基因与生化指标ALT、AST、ALP、GGT、TBIL、DBIL、TBA、ALB的相关性。结果两组间rs55717217、rs6478108、rs4979462、rs1857335位点基因型和等位基因频率分布差异有统计学意义(χ^(2)=16.443、13.463、7.904、7.502、17.313、13.845、16.233、13.687,P<0.05)。rs10114470、rs12235514位点差异无统计学意义(χ^(2)=4.462、3.008、3.445、3.342,P>0.05)。PBC组外周血TL1A水平明显高于健康对照组,差异有统计学意义(t=2.59,P<0.05)。rs4979462位点和rs55717217位点各基因型之间ALT和AST表达水平差异有统计学意义(t=2.12、2.23、3.35、3.36,P<0.05);TL1A水平与AST、ALT、ALP、GGT和TBA成正相关(r=0.202、0.252、0.313、0.328、0.129,P<0.05),与TBIL、DBIL、ALB无明显相关性(P>0.05)。ROC曲线显示TL1A诊断为PBC的曲线下面积(AUC)为0.838。结论TNFSF15基因rs4979462、rs55717217、rs6478108、rs1857335为PBC相关易感基因位点;rs4979462和rs55717217位点的次要等位基因与生化指标ALT、AST的水平升高相关;TL1A与AST、ALT、ALP、GGT和TBA存在明显相关性,并能够为PBC做出准确诊断。

Objective To investigate the relationship between single nucleotide polymorphisms(SNPs)of tumor necrosis factor 15(TNFSF15)gene and its related protein tumor necrosis factor⁃like ligand 1A(TL1A)and primary biliary cholangitis.Methods A total of 120 patients with PBC at Guizhou Provincial People's Hospital from September 2018 to September 2020 were selected as the case group.Simultaneously,120 healthy individuals undergoing medical examinations during the same period at the same hospital were chosen as the control group.The SNP sites(rs55717217,rs6478108,rs4979462,rs10114470,rs1857335,and rs12235514)were screened as research loci.The genotyping of SNPs in the study population was performed by Sanger sequencing technology.The concentration of TL1A in the peripheral blood from the two groups was detected and the correlations between different allele genes at SNP sites and the concentration of serum biochemical indicators including ALT,AST,ALP,GGT,TBIL,DBIL,TBA,ALB,and TL1A were analyzed.Results The SNP polymorphism analysis revealed significant differences in the alleles and distribution frequencies of genotypes rs55717217,rs6478108,rs4979462,and rs1857335 between the PBC group and the healthy control group(χ^(2)=16.443,13.463,7.904,7.502,17.313,13.845,16.233,13.687,P<0.05).However,the differences at the rs10114470 and rs12235514 loci were not statistically significant(χ^(2)=4.462,3.008,3.445,3.342,P>0.05).The concentration of TL1A in peripheral blood in the PBC group was significantly higher than that in the control group and the difference was statistically significant(t=2.59,P<0.05).There was a statistically significant difference in the expression levels of ALT and AST between different genotypes at rs4979462 and rs55717217(t=2.12,2.23,3.35,3.36,P<0.05).The TL1A levels showed a positive correlation with AST,ALT,ALP,GGT,and TBA(r=0.202,0.252,0.313,0.328,0.129,P<0.05).However,there was no obvious correlation with TBIL,DBIL,and ALB(P>0.05).ROC curve analysis revealed that the area under the curve(AUC)for TL1A in diagnosing primary biliary cholangitis(PBC)is 0.838.Conclusion Polymorphisms of rs4979462,rs55717217,rs6478108,and rs1857335 in the TNFSF15 gene are susceptibility loci associated with PBC.The rs4979462 and rs55717217 in TNFSF15 were correlated with high levels of ALT and AST in plasma.TL1A exhibits significant correlations with AST,ALT,ALP,GGT,and TBA,indicating its accuracy in diagnosing PBC.