Leu72Metrs696217基因多态性与非酒精性脂肪性肝病遗传易感性的关系.pdf

159国际消化病杂志 2023 年 6 月 25 日第 43 卷第 3 期 Int J Dig Dis，June 25，2023，Vol.43，No.3 论著 作者单位：518107 中国科学院大学深圳医院（光明）消化内科Leu72Met rs696217 基因多态性与非酒精性脂肪性 肝病遗传易感性的关系章秀丽 李庆群 张绍荣 张楚新【摘要】目的 探讨 Leu72Met rs696217 基因多态性与非酒精性脂肪性肝病（NAFLD）遗传易感性的关系。方法 选择 2019 年 7 月至 2021 年 8 月中国科学院大学深圳医院收治的 125 例 NAFLD 患者作为研究对象（设为 NAFLD 组），另选择同期该院的 104 名健康体检者作为对照组。采用 ELISA 法测定受试者血清白蛋白（ALB）、ALT、AST、总胆红素（TBil）、总胆固醇（TC）、三酰甘油（TG）、凝血酶原时间（PT）和凝血酶原活动度（PTA）水平。应用 ABI Prism 3730 序列检测系统测定 NAFLD 组和对照组 Leu72Met rs696217 基因型，根据分型结果将 NAFLD组分为 GTTT 组（41 例）和 GG 组（84 例），并分析 Leu72Met rs696217 基因型与临床病理特征的关系。采用多因素 logistic 回归模型分析 Leu72Met rs696217 基因多态性与 NAFLD 遗传易感性的关系。结果 与对照组比较，NAFLD 组血清 ALT、AST、TBil、PT、TC、TG 水平均显著升高，而 PTA、ALB 水平均显著降低，差异均有统计学意义（P 均0.05）。NAFLD 组 Leu72Met rs696217 GG 基因型频率高于对照组（67.20%比 17.30%），Leu72Met rs696217 TT 基因型频率低于对照组（16.0%比 73.0%），差异均有统计学意义（P 均0.001）。NAFLD 组 Leu72Met rs696217 G等位基因频率高于对照组（75.6%比 22.1%），Leu72Met rs696217 T 等位基因频率低于对照组（24.4%比 77.9%），差异均有统计学意义（P 均0.001）。与 GTTT 组比 较，GG 组 ALT、AST、TBil、PT、TC、TG 水 平 显 著 升 高，PTA、ALB 水 平 显著降低，且脂肪变性程度、小叶内炎症反应程度、气球样变程度及纤维化程度均显著升高，差异均有统计学意义（P 均0.05）。多因素 logistic 回归模型分析结果显示，Leu72Met rs696217 GG 基因型、Leu72Met rs696217 G 等位基因均是 NAFLD遗传易感性的独立危险因素（P 均0.05）。结论 Leu72Met rs696217 GG 基因型、Leu72Met rs696217 G 等位基因与 NAFLD 遗传易感性具有一定相关性。【关键词】Leu72Met rs696217；基因多态性；非酒精性脂肪性肝病；遗传易感性DOI:10.3969/j.issn.1673-534X.2023.03.006Association of Leu72Met rs696217 gene polymorphism with genetic susceptibility to nonalcoholic fatty liver disease ZHANG Xiuli,LI Qingqun,ZHANG Shaorong,ZHANG Chuxin.Department of Gastroenterology,Shenzhen Hospital,University of Chinese Academy of Sciences,Shenzhen 518107,China【Abstract】Objective This paper is to investigate the association between Leu72Met rs696217 gene polymorphism and the genetic predisposition of nonalcoholic fatty liver disease(NAFLD).Methods A total of 125 patients with NAFLD admitted to the Shenzhen Hospital of the University of Chinese Academy of Sciences between July 2019 and August 2021 were selected and assigned to the study group,and 104 healthy examinees in the same period were selected as the control group.The expression of serum Albumin 160国际消化病杂志 2023 年 6 月 25 日第 43 卷第 3 期 Int J Dig Dis，June 25，2023，Vol.43，No.3(ALB),ALT,AST,total bilirubin(TBil),total cholesterol(TC),triglyceride(TG),prothrombin time(PT)and prothrombin activity(PTA)were detected by ELISA.The Leu72Met rs696217 polymorphism in the NAFLD group and the control group was determined by the ABI Prism 3730 sequence detection system.The NAFLD group was divided into the GTTT group(n41)and the GG group(n84)according to the typing results.The relationship between Leu72Met rs696217 polymorphism and clinicopathological features was analyzed.The multivariate logistic regression model was used to analyze the association between Leu72Met rs696217 polymorphism and NAFLD genetic predisposition.Results Compared with the control group,the expression of ALT,AST,TBil,PT,TC,and TG in the NAFLD group are increased,while that of PTA and ALB are decreased,with statistically significant differences(P0.05).The frequency of Leu72Met rs696217 GG genotype is higher in the NAFLD group than that in the control group(67.20%versus 17.30%),and the frequency of Leu72Met rs696217 TT genotype is lower in the NAFLD group than that in the control group(16.0%versus 73.0%),with statistically significant differences(P0.001).The frequency of Leu72Met rs696217 G allele is higher in the NAFLD group than that in the control group(75.6%versus 22.1%),and the frequency of Leu72Met rs696217 T allele is lower in the NAFLD group than that in the control group(24.4%versus 77.9%),with statistically significant differences(P0.001).Compared with the GT TT group,the expression of ALT,AST,TBil,PT,TC,and TG in the GG group are increased,but that of PTA and ALB are decreased,while the degree of steatosis,inflammatory reaction,balloon-like change and fibrosis are increased,with statistically significant differences(P0.05).The multivariate logistic regression analysis shows that Leu72Met rs696217 GG genotype and Leu72Met rs696217 G allele are independent risk factors for NAFLD genetic predisposition(P0.05).Conclusion Leu72Met rs696217 GG genotype and Leu72Met rs696217 G allele are associated with NAFLD genetic predisposition.【Key words】Leu72Met rs696217;Gene polymorphism;Nonalcoholic fatty liver disease;Genetic susceptibility非 酒 精 性 脂 肪 性 肝 病（NAFLD）是 全 球 范围内常见的慢性肝病。NAFLD 是肝脏代谢综合征的病理表现，包括单纯性非酒精性脂肪性肝病（NAFL）和非酒精性脂肪性肝炎（NASH），可进展至肝纤维化、肝硬化和肝细胞癌（HCC）1。在中国，由于肥胖和老龄化等危险因素的影响，NAFLD的患病率逐年升高。近年来，全基因组关联研究（GWAS）已经对基因组中重要的单核苷酸多态性（SNP）位点与 NAFLD 和脂质代谢的相关性进行了探 索2-3。PNPLA3、KLF6、GCKR、LYPLAL1 等 遗传易感基因已被证实在不同地区和种族的 NAFLD患者遗传易感性中起关键作用4。Leu72Met 是一个具有 200 多个 SNP 位点的多态性基因，位于 3 号染色体的短臂上，由 28 个氨基酸组成。Leu72Met通过影响食欲和食物摄入、脂质和葡萄糖代谢过程、生长激素分泌和炎症反应过程，在长期调节体质量方面发挥重要作用5。研究表明，Leu72Met释放肽的循环水平与肥胖、胰岛素抵抗、2 型糖尿病、高血压和血脂相关6。Leu72Met rs696217 指核苷酸 499 中的鸟嘌呤被腺嘌呤替代，导致氨基酸残基 167（E167K）中的谷氨酸被赖氨酸替代7。研究显示，Leu72Met rs696217 可影响肥胖儿童的血脂水平，且与较低的低密度脂蛋白胆固醇水平显著相关，并可诱导肥胖儿童的肝损伤8。由此推测，Leu72Met rs696217 可能与 NAFLD 的发病具有一定关联性。本文拟探究