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胰岛素样生长因子结合蛋白-3基因rs10225396位点多态性与肝细胞癌易感性的关联性分析
DOI: 10.12449/JCH260417
伦理学声明：本研究方案于2024年5月14日经由延边大学附属医院伦理委员会审批通过（伦理批号：YB.No2024197），患者均签署知情同意书。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：刘世杰负责设计论文框架，起草论文；金光、刘世杰负责实验操作，研究过程的实施；孙数耀、林雨珂负责数据收集，统计学分析、绘制图表；崔鹤松负责论文修改；崔青松负责拟定写作思路，指导撰写文章并最后定稿。
Association of insulin-like growth factor binding protein-3 gene polymorphism at the rs10225396 locus with susceptibility to hepatocellular carcinoma
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摘要:
目的 探究胰岛素样生长因子结合蛋白-3（IGFBP3）基因单核苷酸多态性（SNP）位点rs10225396（A>G）与肝细胞癌易感性的关联，初步揭示其潜在的分子调控机制，为肝细胞癌的早期筛查和精准靶向治疗提供新的遗传生物标志物及理论依据。 方法 选取2009年1月—2016年8月延边大学附属医院和延边肿瘤医院收治的192例肝细胞癌患者（试验组）及同期在延边医院体检中心接受健康体检的190例健康人（对照组）为研究对象。采集研究对象的外周血，从全血中提取DNA后，将符合质量标准的DNA样本送至北京华大基因研究中心有限公司进行Mass ARRAY质谱分析，完成基因分型。计量资料两组间比较采用成组t检验，计数资料两组间比较采用χ2检验。应用二元Logistic回归模型分析IGFBP3基因rs10225396位点SNP与肝细胞癌易感性的关联并计算比值比（OR）及95%置信区间（CI），评估不同基因型携带者发生肝细胞癌的风险。 结果 IGFBP3 基因 rs10225396 位点存在 A、G 两种等位基因及 AA、AG、GG 三种基因型，其基因型分布符合Hardy-Weinberg 遗传平衡定律（χ2=0.072，P=0.789）。基因分层分析显示，在年龄<63岁、男性、有吸烟史、有饮酒史和朝鲜族人群中，IGFBP3基因rs10225396位点AA基因型携带者患肝细胞癌的风险显著增加（P值均<0.001）。二元 Logistic 回归分析显示，调整相关风险因素后，在共显性模型中，与AA基因型相比，AG、GG基因型人群患肝细胞癌的风险降低（P值均<0.001）；在显性模型中，与AA基因型相比，AG+GG基因型人群患肝细胞癌的风险降低（P<0.001）。 结论 通过对吉林省延边朝鲜族自治州地区肝细胞癌患者和健康人群的基因分型分析，证实IGFBP-3基因rs10225396位点的AA基因型与肝细胞癌易感性显著相关，该基因型在特定风险因素下可显著增加肝细胞癌的发生风险，为肝细胞癌的早期筛查和精准治疗提供了潜在的遗传标志物。 -
关键词:
- 癌， 肝细胞 /
- 胰岛素样生长因子结合蛋白质3 /
- 多态性，单核苷酸
Abstract:Objective To investigate the association of the single nucleotide polymorphism （SNP） of the insulin-like growth factor binding protein-3 （IGFBP3） gene at rs10225396 （A>G） locus with the susceptibility to hepatocellular carcinoma， as well as its potential molecular regulatory mechanisms， and to provide novel genetic biomarkers and a theoretical basis for early screening and precise targeted therapy for hepatocellular carcinoma. Methods A total of 192 patients with hepatocellular carcinoma who were admitted to The Affiliated Hospital of Yanbian University and Yanbian Cancer Hospital from January 2009 to August 2016 were enrolled as experimental group， and 190 healthy individuals who underwent physical examination in Physical Examination Center of Yanbian Hospital during the same period of time were enrolled as control group. Peripheral blood samples were collected from all subjects， and after DNA was extracted from whole blood， the DNA samples meeting quality standards were sent to Beijing Genomics Institute Research Center Co.， Ltd.， for Mass ARRAY mass spectrometry， while genotyping was completed. The independent-samples t test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between two groups. A binary Logistic regression model was used to analyze the association of the SNP of the IGFBP3 gene at rs10225396 locus with the susceptibility to hepatocellular carcinoma， and odds ratio （OR） and 95% confidence interval （CI） were calculated to assess the risk of developing hepatocellular carcinoma in individuals carrying different genotypes. Results There were two alleles （G and A） at the rs10225396 locus of the IGFBP3 gene， yielding the three genotypes of AA， AG， and GG， and its genotype distribution was consistent with the Hardy-Weinberg equilibrium （χ²=0.072， P=0.789）. The stratified genetic analysis showed that carriers of the IGFBP3 rs10225396 AA genotype had a significant increased risk of hepatocellular carcinoma among individuals of age <63 years， male sex， smoking history， drinking history， and the Chinese Korean population （all P<0.001）. The binary Logistic regression analysis showed that after adjustment for related risk factors in the codominant model， the population with genotype AG and GG had a significant reduction in the risk of hepatocellular carcinoma compared with the population with genotype AA （P<0.001）， and in the dominant model， the population with genotype AG+GG had a significant reduction in the risk of hepatocellular carcinoma compared with the population with genotype AA （P<0.001）. Conclusion Through a genotyping analysis of hepatocellular carcinoma patients and healthy individuals in Yanbian Korean Autonomous Prefecture of Jilin Province， China， this study shows that genotype AA at rs10225396 locus of the IGFBP3 gene is significantly associated with the susceptibility to hepatocellular carcinoma， and this genotype can significantly increase the risk of developing hepatocellular carcinoma with the presence of specific risk factors， which provides a potential genetic marker for early screening and precise treatment of hepatocellular carcinoma. -
图 1 胰岛素样生长因子结合蛋白-3基因rs10225396位点测序聚类散点图
Figure 1. Scatterplot of clustering by sequencing of IGFBP3 gene at locus rs10225396
注： Mb，兆碱基对；AC，序列登录号；p，短臂；p12.3，短臂1区2带3亚带。
图 3 7号染色体rs10225396位点的调控元件分布
Figure 3. Distribution of regulatory elements at the rs10225396 locus on chromosome 7
图 4 胰岛素样生长因子结合蛋白-3不同表达水平的生存率
Figure 4. Survival rates for different expression levels of IGFBP3
注： a，AA基因型；b，AG基因型；c，GG基因型；图中蓝色虚线标注的峰为检测得到的目标基因型。
图 5 rs10225396基因型峰值图
Figure 5. Peak plot of rs10225396 genotype
表 1 研究对象一般情况比较
Table 1. Comparison of the general conditions of the study population
因素 试验组
（n=192）对照组
（n=190）统计值 P值 年龄（岁） 61.23±10.17 62.37±10.93 t=1.055 0.292 性别［例（%）］ χ2=2.322 0.128 男 142（74.0） 127（66.8） 女 50（26.0） 63（33.2） 吸烟情况［例（%）］ χ2=10.717 <0.001 吸烟 113（58.9） 80（42.1） 不吸烟 79（41.1） 110（57.9） 饮酒情况［例（%）］ χ2=44.624 <0.001 饮酒 121（63.0） 55（28.9） 不饮酒 71（37.0） 135（71.1） 民族［例（%）］ χ2=15.918 <0.001 朝鲜族 117（60.9） 84（44.2） 汉族 75（39.1） 106（55.8） 
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表 2 IGFBP3基因rs10225396与肝细胞癌易感性关系分层分析
Table 2. Stratified analysis of the association between IGFBP3 gene rs10225396 and susceptibility to Hepatocellular Carcinoma
因素 基因型［试验组（n=192）/对照组（n=190）］ AA/AG+GG模型
OR（95%CI）P值 AA AG GG 年龄（例） <63岁 46/19 40/55 8/23 3.934（2.060～7.492） <0.001 ≥63岁 49/30 39/48 10/15 2.100（1.166～3.781） 0.013 性别（例） 男 71/30 58/64 13/33 3.233（1.912～5.467） <0.001 女 24/19 21/39 5/5 2.138（0.987～4.630） 0.054 吸烟情况（例） 吸烟 56/23 46/53 11/28 3.460（1.914～6.254） <0.001 不吸烟 39/26 33/50 7/10 2.250（1.189～4.256） 0.013 饮酒情况（例） 饮酒 62/19 48/41 11/21 3.429（1.835～6.409） <0.001 不饮酒 33/30 31/62 7/17 2.287（1.221～4.285） 0.010 民族（例） 汉族 35/32 35/61 5/20 2.215（1.202～4.080） 0.011 朝鲜族 60/17 44/42 13/18 3.715（1.941～7.111） <0.001 注：IGFBP3，胰岛素样生长因子结合蛋白-3；G，鸟嘌呤；A，腺嘌呤；OR，比值比；CI，置信区间。
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表 3 IGFBP3 rs10225396（A>G）基因型在肝细胞癌试验组与对照组中的频率分布
Table 3. Frequency distribution of IGFBP3 rs10225396 （A>G） genotypes in hepatocellular carcinoma cases and controls
基因型组合方式 试验组（n=192） 对照组（n=190） χ2 值 P值 共显性模型［例（%）］ 24.992 <0.001 AA 95（49.5） 49（25.8） AG 79（41.1） 103（54.2） GG 18（9.4） 38（20.0） 隐性模型［例（%）］ 8.617 0.003 AA+AG 174（90.6） 152（80.0） GG 18（9.4） 38（20.0） 显性模型［例（%）］ 22.891 <0.001 AA 95（49.5） 49（25.8） AG+GG 97（50.5） 141（74.2） 注：IGFBP3，胰岛素样生长因子结合蛋白-3；SNP，单核苷酸多态性；G，鸟嘌呤；A，腺嘌呤；A>G，A→G 碱基替换。
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表 4 基于Logistic回归分析IGFBP3 rs10225396（A>G）多态性与肝细胞癌发病风险的关联
Table 4. Logistic regression analysis of the association between IGFBP3 rs10225396 （A>G） polymorphism and hepatocellular carcinoma risk
基因型组合方式 OR（95%CI） P值 调整OR（95%CI） P值 共显性模型 AA 1.000 1.000 AG 0.396（0.252～0.622） <0.001 0.410（0.255～0.659） <0.001 GG 0.244（0.126～0.472） <0.001 0.214（0.106～0.432） <0.001 隐性模型 AA+AG 1.000 1.000 GG 0.414（0.227～0.755） 0.004 0.356（0.187～0.677） 0.002 显性模型 AA 1.000 1.000 AG+GG 0.355（0.231～0.546） <0.001 0.356（0.227～0.560） <0.001 注：IGFBP3，胰岛素样生长因子结合蛋白-3；SNP，单核苷酸多态性；G，鸟嘌呤；A，腺嘌呤；A>G，A→G碱基替换；OR，比值比；CI，置信区间。
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