Table1_Comprehensive investigating of mismatch repair genes (MMR) polymorphisms in participants with chronic hepatitis B virus infection.pdf

Background and aim: In this study, we focused on the relationship between single nucleotide polymorphisms in MMR genes and the occurrence and development of HBV infection.Materials and methods: A total of 3,128 participants were divided into five groups: negative control group (NeC), spontaneous clearance group (SC), chronic hepatitis B group (CHB), liver cirrhosis group (LC) and hepatocellular carcinoma group (HCC), CHB, liver cirrhosis and hepatocellular carcinoma constitute HLD. We conducted three case-control studies: NeC (840 cases) vs. HLD (1792 cases), SC (486 cases) vs. HLD (1792 cases) and CHB + LC (1,371 cases) vs. HCC (421 cases). 11 polymorphic loci in MLH1, MLH3, MSH5, PMS1 and PMS2 were involved in genotyping by Sequenom MassArray. The SNPStats performed Hardy-Weinberg equilibrium test. Linkage disequilibrium patterns were visualized using Haploview4.2. The GMDR (v0.9) was conducted to generalized multifactor dimension reduction analysis. The correlation, multiplicative interaction and additive interaction analyses were calculated by Logistic Regression through SPSS21.0. Matrix and programmed excel were also involved in the calculation of additive interaction.Results: In NeC vs. HLD group, MSH5-rs1150793(G) was a risk base to HBV susceptibility (nominal p = 0.002, OR = 1.346). We found multiplicative interaction between MLH1-rs1540354 (AA + AT) and PMS1-rs1233255 (AA) (nominal p = 0.024, OR = 1.240). There was additive interaction between PMS1-rs1233255 (AA) and PMS1-rs256554(CA + CC). In SC vs. HLD group, MLH1-rs1540354 (TT) was a risk genotype (nominal p < 0.05, OR>1). Through haplotype analysis, we found the linkage disequilibrium of three loci in MLH1. The results of GMDR showed the optimal five-locus model about the spontaneous clearance of HBV. In CHB + LC vs. HCC group, PMS2-rs12112229(A) was related to the cancerization of liver.Conclusion: We found rs1150793(G), rs1540354(T) and rs12112229(A) were significantly related to HBV susceptibility, spontaneous clearance of HBV and cancerization after infection, respectively.

背景与目标：本研究着眼于MMR基因中单核苷酸多态性与乙型肝炎病毒（HBV）感染的发生与发展之间的关联。研究材料与方法：共纳入3,128名参与者，分为五组：阴性对照组（NeC）、自发清除组（SC）、慢性乙型肝炎组（CHB）、肝硬变组（LC）和肝细胞癌组（HCC），其中CHB、肝硬变和肝细胞癌共同构成肝衰竭（HLD）。本研究开展了三项病例对照研究：NeC组（840例）与HLD组（1792例）对照，SC组（486例）与HLD组（1792例）对照，以及CHB+LC组（1371例）与HCC组（421例）对照。通过Sequenom MassArray对MLH1、MLH3、MSH5、PMS1和PMS2中的11个多态性位点进行基因分型。采用SNPStats进行Hardy-Weinberg平衡检验。利用Haploview4.2软件可视化连锁不平衡模式。采用GMDR（v0.9）进行广义多因素降维分析。通过SPSS21.0的Logistic回归进行相关性、乘性交互作用和加性交互作用的计算。矩阵和编程Excel亦用于加性交互作用的计算。结果：在NeC组与HLD组对照中，MSH5-rs1150793(G)为HBV易感性的风险基因型（名义p值=0.002，OR=1.346）。发现MLH1-rs1540354（AA+AT）与PMS1-rs1233255（AA）之间存在乘性交互作用（名义p值=0.024，OR=1.240）。PMS1-rs1233255（AA）与PMS1-rs256554（CA+CC）之间存在加性交互作用。在SC组与HLD组对照中，MLH1-rs1540354（TT）为风险基因型（名义p值<0.05，OR>1）。通过连锁不平衡分析，发现MLH1中的三个位点的连锁不平衡。GMDR的结果显示关于HBV自发清除的最佳五位点模型。在CHB+LC组与HCC组对照中，PMS2-rs12112229(A)与肝细胞癌的发生相关。结论：本研究发现rs1150793(G)、rs1540354(T)和rs12112229(A)分别与HBV易感性、HBV自发清除和感染后的癌变显著相关。