Abstract
王立芹,郭维恒,郭志旺,秦璞,张蕊,朱晓敏,刘殿武.PNPLA3、TM6SF2基因多态性及其与吸烟、饮酒交互作用对HBV相关肝癌的影响[J].Chinese journal of Epidemiology,2018,39(12):1611-1616
PNPLA3、TM6SF2基因多态性及其与吸烟、饮酒交互作用对HBV相关肝癌的影响
Effects of PNPLA3, TM6SF2 gene polymorphisms and its interactions with smoking and alcohol drinking on hepatitis B virus-associated hepatocellular carcinoma
Received:June 19, 2018  
DOI:10.3760/cma.j.issn.0254-6450.2018.12.014
KeyWord: 乙型肝炎病毒  肿瘤,肝  patatin样磷脂酶域3  6号跨膜超家族成员2  交互作用
English Key Word: Hepatitis B virus  Carcinoma, hepatocellular  Patatin-like phospholipase domain containing 3  Transmembrane 6 superfamily member 2  Interaction effect
FundProject:河北省自然基金重大项目(H2016206576)
Author NameAffiliationE-mail
Wang Liqin Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China  
Guo Weiheng Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China  
Guo Zhiwang Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China  
Qin Pu Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China  
Zhang Rui Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China  
Zhu Xiaomin Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China  
Liu Dianwu Hebei Key Laboratory of Environment and Population Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 050031, China liudianw@hebmu.edu.cn 
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Abstract:
      目的 探讨PNPLA3、TM6SF2基因多态性及其与吸烟、饮酒交互作用对HBV相关肝癌(hepatitis B virus-associated hepatocellular carcinoma,HBV-HCC)的影响。方法 收集2010年1月至2014年3月HBV-HCC患者、慢性乙型肝炎(乙肝)患者(CHB)、肝硬化患者(LC)以及健康体检者的血液标本,应用飞行质谱技术检测patatin样磷脂酶域3(PNPLA3)基因位点rs738409和6号跨膜超家族成员2(TM6SF2)基因位点rs58542926的单核苷酸多态性(SNP)。利用在线SNP stats寻找基因多态性的最优赋值方法;检验SNP是否符合哈-温(H-W)遗传平衡定律;采用多分类logistic回归分析PNPLA3和TM6SF2多态性及吸烟、饮酒因素对HBV-HCC的影响,采用叉生分析和二分类logistic回归分析探讨基因-基因、基因-吸烟、饮酒交互作用对HBV-HCC的影响。结果 H-W遗传平衡检验结果显示,CHB组rs738409位点的基因型频率分布不符合H-W遗传平衡定律(χ2=11.980,P<0.005),CHB组rs58542926位点、HBV-HCC组和LC组rs738409和rs58542926位点均符合H-W遗传平衡定律;调整年龄、性别的影响后,与健康体检者相比,HBV-HCC组rs58542926突变的OR=1.659,95% CI:1.026~2.684,P=0.039。与CHB组相比,HBV-HCC组饮酒的OR=1.680,95% CI:1.121~2.519,P=0.012。与LC组相比,HBV-HCC组饮酒与吸烟的OR值(95% CI)分别为1.539(1.071~2.213)和1.453(1.005~2.099)。交互作用分析显示,HBV-HCC组与CHB+LC组相比,rs738409与rs58542926交互作用的叉生分析相加模型OR=1.548(U=1.885,P=0.029),logistic回归相乘模型OR=1.658(P=0.024);饮酒与rs738409的交互作用叉生分析,饮酒且rs738409突变相加模型OR=1.811(U=1.965,P=0.024),相乘模型无统计学意义;logistic回归相乘模型吸烟与饮酒的交互作用OR=1.756(P<0.001)。结论 TM6SF2基因突变、吸烟、饮酒是HBV-HCC的危险因素,PNPLA3与TM6SF2基因都突变、饮酒并且吸烟是HBV-HCC的危险因素。PNPLA3的单基因突变可以减弱饮酒对HBV-HCC的危害。
English Abstract:
      Objective To explore the SNP effects of patatin-like phospholipase domain which containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) gene, environmental effects of smoking, alcohol drinking and interaction between gene-gene, gene-environment and drinking-smoking on hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). Methods We collected anticoagulant peripheral blood from patients of HBV-HCC, chronic hepatitis B (CHB), liver cirrhosis (LC) and from healthy controls to detect the single nucleotide polymorphism (SNP) of patatin-like phospholipase domain containing 3 (PNPLA3) gene loci rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) gene loci rs58542926, using the flight mass spectrometry method. The optimal assignment value of gene polymorphisms was defined by using the online SNP stats. Hardy-Weinberg (H-W) balance was tested for SNP. Effects of the genetic and environmental factors to HBV-HCC were analyzed by using the multiple classification logistic regression method. The gene-gene, gene-smoking and alcohol drinking interaction effects were investigated by Fork-Life analysis and binary logistic regression methods. Results The frequency distribution of CHB group rs738409 loci seemed not in conformity with the H-W balance (χ2=11.980, P<0.005). Two loci frequency distributions in the other groups were all in accordandce with the H-W balance. After adjusting for influences on age and sex and comparing to the healthy group, the rs58542926 mutation appeared as OR=1.659, 95% CI:1.026-2.684, P=0.039, in the HBV-HCC group. When comparing to CHB group, the HBV-HCC group presented that drinking as OR=1.680, 95% CI:1.121-2.519, P=0.012. When comparing to the LC group, the ORs of drinking and smoking were 1.539 (1.071-2.213) and 1.453 (1.005-2.099) respectively, in the HBV-HCC group. When comparing to the CHB+LC group, interactions between the HBV-HCC group were found rs738409 and rs58542926 on additive model OR=1.548 (U=1.885, P=0.029) and OR=1.658 (P=0.024) on logistic regression model while drinking was rs738409 on interaction additive model with OR=1.811(U=1.965, P=0.024). As for drinking and mutation of rs738409, the multiplication model of logistic regression showed no statistically significant differences. Interaction between smoking and drinking appeared as OR=1.756 (P<0.001) in the logistics regression multiplication model. Conclusions Factors as mutation of TM6SF2, smoking and drinking all appeared as risk factors for HBV-HCC. Mutations of both PNPLA3 and TM6SF2, together with smoking and drinking all served as risk factors for HBV-HCC. However, the mutation of single PNPLA3 appeared as a protective factor on HBV-HCC.
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