Advances in Clinical Medicine
Vol. 14  No. 05 ( 2024 ), Article ID: 86369 , 9 pages
10.12677/acm.2024.1451434

SOCS1 rs243330位点多态性与非酒精性脂肪性肝病的相关性研究

崔禹,赵真真*

青岛大学青岛市市立医院,山东 青岛

收稿日期:2024年4月9日;录用日期:2024年5月4日;发布日期:2024年5月11日

摘要

本文主要探究中国青岛地区人群细胞因子信号传导抑制因子1 (suppressors of cytkine signaling 1, SOCS1) rs243330位点多态性与非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)易感性的相关性。方法:纳入2022年06月~2023年06月青岛市市立医院收入院的NAFLD患者220例,健康对照者112例。提取受试者血液中的DNA,使用多聚酶链反应(polymerase chain reaction, PCR)的方法扩增DNA,并检测SOCS1基因rs243330位点的基因型。收集并分析患者的所有临床数据以及与代谢状态相关的指标。使用χ2检验分析基因型及等位基因频率。符合正态分布的计量资料采用t检验,不符合正态分布的计量资料采用Wilcoxon秩和检验进行组间比较。结果:NAFLD组和对照组SOCS1 rs243330位点的基因型与等位基因分布差异均无统计学意义。结论:在青岛地区人群中,SOCS1 rs243330位点多态性与NAFLD的无显著相关性。

关键词

细胞因子信号传导抑制因子1,非酒精性脂肪性肝病,单核苷酸多态性

Study on Association between SOCS1 rs243330 Polymorphisms and Non-Alcoholic Fatty Liver Disease

Yu Cui, Zhenzhen Zhao*

Qingdao Municipal Hospital, Qingdao University, Qingdao Shandong

Received: Apr. 9th, 2024; accepted: May 4th, 2024; published: May 11th, 2024

ABSTRACT

This study was aimed to explore the correlation between cytokine signaling inhibitor 1 rs243330 polymorphism and susceptibility to non-alcoholic fatty liver disease in Qingdao, China. Methods: 220 patients with NAFLD and 112 healthy controls admitted to Qingdao Municipal Hospital from June 2022 to June 2023 were included. DNA was extracted from the subjects’ blood, amplified by polymerase chain reaction (PCR), and genotype of SOCS1 gene rs243330 was detected. All clinical data of the patient and indicators related to metabolic status were collected and analyzed. Genotype and allele frequency were analyzed using χ2 test. T-test was used for measurement data conforming to normal distribution, and Wilcoxon rank sum test was used for comparison between groups for measurement data not conforming to normal distribution. Results: There were no significant differences in genotype and allele distribution of SOCS1 rs243330 between NAFLD group and control group. Conclusion: There is no significant correlation between SOCS1 rs243330 polymorphism and NAFLD in Qingdao population.

Keywords:Suppressors of Cytkine Signaling 1, Non-Alcoholic Fatty Liver Disease, Single Nucleotide Polymorphism

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD),是当前世界范围内最常见的肝病病因之一 [1] 。NAFLD是指排除大量饮酒或其他病理原因的情况下,以肝细胞内脂肪的过量堆积与沉积为特征的一种临床病理综合征 [2] 。NAFLD的患者中一部分会进展为非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH),NASH是NAFLD的炎症亚型,其特征是脂肪变性、肝细胞损伤(气球状突起)和伴或不伴有纤维化的炎症 [3] 。许多先前的研究认为NASH是一种良性疾病 [4] 。然而,随着证据的积累,NASH是一种良性疾病的概念受到了挑战,它现在被认为是一种进行性疾病。最近的数据显示,近25%的NASH患者可发展为肝纤维化 [5] ;在另一项研究中,NASH患者接受了连续活检,25例脂肪变性患者中64%的人群在3.7年后迅速进展为肝硬化 [6] 。在一项比较NAFLD和NASH的荟萃分析中,进展为不同肝纤维化阶段的患者比例相似(分别为39.1%和34.5%) [7] 。可见NASH有一定风险发展为肝硬化、肝衰竭甚至肝细胞癌(hepatocellular carcinoma, HCC) [8] ,这也使NAFLD正在成为肝脏疾病终末期患者肝移植的主要原因之一 [9] 。HCC是全球癌症患者死亡的第四大原因,也是癌症患者寿命减少的第二大原因 [10] 。流行病学显示,在过去四十年中,NAFLD的全球流行率估计为30%,亚洲地区为28%,患病率从24%上升到38% [12] 。NAFLD及其相关并发症在全世界造成的医疗负担正在逐年增加,如何从根源预防NAFLD的发生、延缓甚至控制NAFLD的进展是目前全球范围内的挑战 [12] 。

细胞因子信号传导抑制剂1 (suppressors of cytkine signaling 1, SOCS1)是调节蛋白SOCS家族的八个成员之一,由早期反应基因对外部刺激(如细胞因子、生长因子和toll样受体)的反应合成 [13] 。SOCS1的主要作用是调节Janus激酶/信号转导与转录激活因子(janus kinase/signal transducers and activators of transcription, JAK/STAT)信号通路,其可以阻止机体免疫细胞过激的产生免疫反应,还可调节同一种细胞因子在不同靶细胞中的作用效应 [14] [15] 。SOCS1蛋白在介导免疫细胞和代谢器官(如肝脏和脂肪组织)的炎症反应中发挥重要作用 [16] 。SOCS1已被证明与肝脏多种疾病的病理生理学有关,在原发性胆汁性胆管炎(Primary Biliary Cholangitis, PBC)中,肝脏SOCS1的表达受到微小RNA-155的抑制,这可能导致促炎细胞因子如肿瘤坏死因子α (tumor necrosis factors α, TNF α)和白细胞介素1β (interleukin 1β, IL-1β)的产生增加 [17] 。也有研究表明,乙型肝炎病毒(hepatitis B virus, HBV)表面的X蛋白能够通过调节SOCS1的水平,促进肝癌细胞的上皮–间质转化 [18] ,通过这些研究说明SOCS1能够直接或间接地影响肝脏炎症及肝细胞癌等疾病进程的发生与发展。为了探究SOCS1 rs243330位点多态性与中国青岛地区汉族人群NAFLD易感性的相关性展开此研究。

2. 研究对象与方法

2.1. 研究对象

所有受试者均抽取禁食12 h后的全血,然后送血样到检验科,检测指标包括总胆红素(TBiL)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰转移酶(GGT)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)。采用聚合酶链式反应对目的基因进行扩增,并对TLR4 rs1927914位点多态性分析。PCR引物序列:上游引物:ACGTTGGATGACAGTAGAACTATCTAGGAC;下游引物:ACGTTGGATGGGAAAGTAGCAAGTGCAATG。提取DNA后,由博淼生物科技(北京)有限公司采用基于Massarray技术进行位点核苷酸多态性测序。

2.2. 研究方法

2.2.1. 受试者相关血液指标的收集

受试者空腹12 h后晨起由医护人员取静脉血4 ml,将静脉血取出一部分分别保存到2个EDTA抗凝管中用于后续研究;剩余样本分为两管,一管血液样本送往青岛市市立医院检验科进行生物化学指标检测,包括碱性磷酸酶(ALP)、γ-谷氨酰转移酶(GGT)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、总胆红素(TBil)、空腹血糖(FPG)、总胆固醇(TC)、甘油三脂(TG)、低密度脂蛋白胆固醇(LDL)、高密度脂蛋白胆固醇(HDL)、载脂蛋白A1 (Apo A1)、载脂蛋白B (Apo B)。一管血液样本用于实验室内行DNA提取及基因型鉴定。

2.2.2. 基因位点的测定

采用聚合酶链式反应对目的基因进行扩增,并对SOCS1 rs243330位点多态性分析。PCR引物序列:上游引物:5’-ACGTTGGATGGGGAAATCTATGAGGAAGGG-3;下游引物:5’-ACGTTGGATGGTGCATTCTCAGACGTGATG-3’。实验室内提取DNA后,由博淼生物科技(北京)有限公司采用基于Massarray技术进行位点核苷酸多态性测序。

2.3. 统计学方法

基因型及等位基因频率分布等定性资料两组间比较应用卡方检验(χ2)。符合正态分布的数据使用均数± 标准差表示,不符合正态分布的数据则用四分位数表示,即P50 (P25, P75)。若两组连续变量都符合正态性则使用t检验进行组间比较;否则采用非参数检验进行组间比较。使用二元Logistic回归模型来评估SOCS1 rs243330位点SNPs与NAFLD易感性之间的关系,并计算回归模型的比值比(odds ratio, OR)及95%可信区间(95% redibility interval, 95% CI)。认为P < 0.05时结果有显著差异。

3. 结果

3.1. 健康对照组和NAFLD组间的临床资料及生物化学指标比较

本研究共纳入332人,其中220例NAFLD患者,112例健康体检者。NAFLD组和健康对照组的临床资料见表1。其中所有定量资料均符合非正态分布,两组间性别、TC、LDL、TBil、ApoB差异无统计学意义(P均>0.05)。NAFLD组的年龄、BMI、FPG、ALT、AST、GGT、ALP、TG水平显著高于健康对照组,而NAFLD组的HDL与ApoA1则低于健康对照组(P均<0.05) (见表1)。

Table 1. Clinical date and biochemical parameters of all subjects

表1. 所有受试者的临床资料及生物化学指标

注:① 缩写:丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆红素(TBil)、总胆固醇(TC)、甘油三脂(TG)、γ-谷氨酰转移酶(GGT),碱性磷酸酶(ALP)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、空腹血糖(FPG)、载脂蛋白A1 (ApoA1)、载脂蛋白B (ApoB);② 符合正态分布的数据资料使用均数±标准差来表示,不符合正态分布的资料使用p50 (p25, p75)表示;③ 以P < 0.05为差异有统计学意义。

3.2. SOCS1 rs243330基因型及等位基因在NAFLD组和健康对照组的频率分布

基因测序发现SOCS1 rs243330有三种基因型(AA、AG、GG),χ2检验显示SOCS1 rs243330的基因型在NAFLD组及健康对照组中的分布均符合Hardy-weinberg平衡法则(χ2 = 0.730, P = 0.694),具有群体代表性。经检验,SOCS1基因rs243330的基因型、隐性基因模型、显性基因模型和等位基因频率的分布差异在NAFLD组和健康对照组之间无统计学意义(见表2)。

Table 2. SOCS1 rs243330 allele and genotype frequency distribution

表2. SOCS1 rs243330等位基因和基因型频率分布

3.3. SOCS1 rs243330基因多态性与NAFLD易感性分析

应用二元logistic回归模型分析SOCS1基因rs243330位点与NAFLD易感性的关系结果,在完成年龄、性别、BMI校正后没有统计学意义(见表3)。

Table 3. Logistic regression analysis of risk factors for NAFLD

表3. NAFLD危险因素的Logistic回归分析结果

注:① ORa、95%CIaPa值为校正性别、年龄、BMI后的OR、95%CI及P值;② P < 0.05认为差异具有统计学意义。

3.4. 所有受试者中AA基因携带者与非携带者之间各项数据比较

在所有受试者中,各项定量资料均符合非正态分布。对SOCS1 rs243330不同基因型之间生物化学指标进行比较,结果显示,在所有受试者中,SOCS1 rs243330位点AA基因型携带者与非携带者之间在ALP水平之间差异显著,AA基因型携带者拥有更高的ALP水平(P < 0.05),而在BMI、FPG、ALT、AST、GGT、TC、TG、LDL、HDL、TBil之间两者没有统计学差异(P均>0.05) (见表4)。

Table 4. Comparison of various indexes between AA genotype carriers and non-carriers in all subjects

表4. 所有受试者中AA基因型携带者与非携带者各项指标比较

注:① 符合正态分布的资料用均数±标准差表示,符合非正态分布的资料用p50 (p25, p75)表示;② 以P < 0.05认为差异有统计学意义。

4. 讨论

NAFLD是指在没有其他已知原因(如过量饮酒、病毒性肝炎或服用可能导致脂肪肝的药物等)的情况下出现的一系列可见组织学活检及影像学变化的肝脏疾病的总称 [19] 。由于NAFLD本质上是一种代谢性疾病,近年来国际上部分学者认为也可以将其命名为代谢相关性脂肪性肝病(metabolic dysfunction-associated fatty liver disease, MAFLD) [20] 。持续增加的儿童和成人肥胖人数及逐年升高的糖尿病患病率,导致NAFLD高危人群的数量呈指数上升 [21] 。其中一部分NAFLD患者会发展为NASH,随着时间推移,一部分NASH患者会进展成为肝硬化或肝细胞癌 [22] 。尽管肝纤维化程度的非侵入性评估技术(如瞬态弹性超声成像)正不断成熟且逐步在临床推广应用 [23] ,肝活检等侵入性手术仍然是评估肝脏健康的金标准 [24] 。在临床试验中,识别可获得的非成像工具和准确的生物标志物将有助于验证新兴的治疗方法。

细胞因子信号传导抑制剂(SOCS)是细胞因子和生长因子信号传导的调节剂,其异常调节与多种疾病有关 [25] 。研究报道称肥胖T2DM患者中SOCS基因的mRNA表达增加,这表示SOCS可能与T2DM的发生与进展有关 [26] 。Xu等人 [27] 研究发现SOCS可以通过负调控JAK/STAT3信号通路抑制多形性胶质母细胞瘤(glioblastoma multiforme, GBM)细胞增殖和血管生成。在SOCS家族中,SOCS1已被广泛研究。最初,SOCS1被认为是细胞因子信号传导的负反馈调节因子,通过SOCS1激酶抑制区(KIR)和Src同源性2 (SH2)结构域对于与受体相关JAK1、JAK2和TYK2酪氨酸激酶的相互作用和抑制来调节JAK/STAT炎症信号通路 [28] 。随着研究的进展,人们发现SOCS1在细胞的活化、增殖与分化中也起到重要作用 [29] 。因此,大量研究推测SOCS1可能在调节肿瘤生长和增殖中发挥作用,如肝细胞癌 [30] [31] 、黑色素瘤 [32] [33] 、胃癌 [34] 、前列腺癌 [35] 等。近年来,随着GWAS等基因组学相关研究的进展,SOCS1不同突变基因层面特征正逐渐明确,目前人们研究发现,SOCS1基因在肝脏中凸显相关的主要作用是通过负反馈回路对于肝脏炎症及免疫反应进行调节,进而对于肝脏疾病出现及进展进行调节 [36] [37] [38] 。Starr等人 [39] 通过实验验证发现SOCS1基因缺失的小鼠出生后,体重非常低,出现肝脏脂肪变性,伴多个器官炎症浸润,且部分会在断奶前死亡。早在2008年,Gylvin等人 [40] 就提出在丹麦高加索人群中SOCS1 rs243330多态性与肥胖及NAFLD具有显著相关性。Agnieszka等人 [41] 通过进一步研究发现在矫正年龄、性别等因素后,与A等位基因组相比,超重和肥胖的NAFLD患者的G等位基因频率显著较高,SOCS1 rs243330多态性AA基因型频率较低,这表明G等位基因是代谢性肝病的危险等位基因。Agnieszka等人还发现了一个有趣的现象,与GG基因型人群中的NAFLD相反,这种SOCS1变体的AA基因型使携带者容易肥胖。然而国内尚无对于SOCS1基因rs243330位点多态性与NAFLD关系的研究调查。为了分析汉族人群遗传层面基因位点多样性与NAFLD疾病易感性的关系,故展开此研究。

本研究首次在中国人群中筛选出符合纳入排除标准的332名青岛汉族人群进行了SOCS1 rs243330位点多态性与NAFLD易感性的相关性分析。结果显示,该位点等位基因及基因型的分布在NAFLD人群和健康人群之间的差异没有统计学意义,其位点多态性亦与NAFLD疾病易感性无显著相关性。然而在对照人群中,G等位基因的携带与AST升高有关,这符合Agnieszka等人通过研究得到的G等位基因为NAFLD危险等位基因的发现。本研究得到的结论,即SOCS1 rs243330位点多态性与NAFLD易感性无关,这与Agnieszka等人的研究结论存在差异。我们认为产生该结果的差异原因为,本次研究的研究对象为中国青岛地区汉族人群,而Agnieszka等人及现在正在研究的大多数的国家与地区的主要研究对象则为欧洲波兰高加索人群,且本研究相较其他国外研究在样本量上仍有差距,因此我们推测,结果不一致可能与地域、人种、样本量等因素导致的位点多态性差异的表现相关。本研究存在一定的局限性,下一步研究应招募更多数量受试者,尽可能将随机纳入的受试者进按照不同年龄、BMI、性别进行分组对比,扩大地域和民族范围,同时完善受试者的肝活组织检查,来进一步研究SOCS1 rs243330基因多态性对NAFLD的影响。此外,我们已知SOCS1 rs243330位点多态性与T2DM的发病与进展有明确的关联,且NAFLD与T2DM之间机制的联系也随着研究展开而越发密切,下一步我们可以将研究的方向进一步展开,通过对于加入T2DM患者的临床数据进行进一步统计分析,从而将两大当前世界面临的临床疾病联合研究,探索新的疾病进展相关性可能。本研究存在一定的局限性,下一步研究应招募更多数量受试者,尽可能将随机纳入的受试者进按照不同年龄、BMI、性别进行分组对比,扩大地域和民族范围,同时完善受试者的肝活组织检查,来进一步研究SOCS1 rs243330基因多态性对 NAFLD的影响。此外,我们已知SOCS1 rs243330位点多态性与T2DM的发病与进展有明确的关联,且NAFLD与T2DM之间机制的联系也随着研究展开而越发密切,下一步我们可以将研究的方向进一步展开,通过对于加入T2DM患者的临床数据进行进一步统计分析,从而将两大当前世界面临的临床疾病联合研究,探索新的疾病进展相关性可能。

5. 结论

综上所述,本研究创新之处在于首次在中国青岛汉族人群中,探讨了SOCS1 rs243330基因多态性与NAFLD易感性并不具有显著相关性。也为进一步探索SOCS1基因多态性与NAFLD及其他临床疾病相关性奠定基础。

文章引用

崔 禹,赵真真. SOCS1 rs243330位点多态性与非酒精性脂肪性肝病的相关性研究
Study on Association between SOCS1 rs243330 Polymorphisms and Non-Alcoholic Fatty Liver Disease[J]. 临床医学进展, 2024, 14(05): 352-360. https://doi.org/10.12677/acm.2024.1451434

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  42. NOTES

    *通讯作者。

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