TM6SF2 rs58542926 E167K 单核苷酸多态性与肝硬化、肝细胞癌易感性的关系

邴 浩，沈剑华，李异玲

中国医科大学附属第一医院消化内科，辽宁 沈阳 110001

TM6SF2 rs58542926 E167K 单核苷酸多态性与肝硬化、肝细胞癌易感性的关系

邴 浩，沈剑华，李异玲

中国医科大学附属第一医院消化内科，辽宁 沈阳 110001

跨膜蛋白6超家族成员2(transmembrane 6 superfamily member 2，TM6SF2)位于第19号染色体上，主要表达于小肠及肝脏，参与脂质的调控。rs58542926处基因突变致其编码的蛋白表达降低。研究显示，TM6SF2 rs58542926 E167K单核苷酸多态性与肝内脂质含量、血清肝酶含量及肝纤维化均有相关性，是非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)的独立危险因素。最近研究发现，TM6SF2 rs58542926 E167K单核苷酸多态性与肝硬化及肝细胞癌也具有一定相关性。

肝硬化；肝细胞癌；TM6SF2 rs58542926 E167K；易感性

肝细胞癌(hepatocellular carcinoma，HCC)在全世界癌症发病率居第6位，占癌症死亡原因的第3位，是最常见的消化道肿瘤，也是肝硬化患者的重要死因[1]。中国有世界上约55%的HCC患者，其5年总体生存率(overall survival，OS)只有7%[2]。HCC主要病因为慢性病毒性(HBV或HCV)肝炎[3]，非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)及非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)相关性肝癌的发病率也在不断增加。

随着精准医学及全基因组关联分析(genome-wide association studies，GWAS)的发展，遗传因素不断得到重视。PNPLA3已经被证明与NAFLD、肝硬化及HCC的发展具有相关性[4-6]。近年来发现TM6SF2 rs58542926 E167K也是NAFLD发生的易感因素，本文拟就TM6SF2基因与肝硬化及HCC的关系作一概述。

1 TM6SF2的一般特性

1.1 TM6SF2 rs58542926 E167K的单核苷酸多态性 跨膜蛋白6超家族2(TM6SF2)位于第19号染色体上(19p12)，编码一个由351个氨基酸构成的蛋白，该蛋白为多次跨膜结构，主要表达于肝脏、小肠及肾脏，在小肠中表达最多。TM6SF2 rs58542926 E167K突变(EK/KK)使其第499号核苷酸由胞嘧啶(C)错义突变为胸腺嘧啶(T)，导致其编码的蛋白第167残基由谷氨酸(E)突变为赖氨酸(K)[7-8]，突变大致发生在蛋白第5个跨膜结构[9]，使该蛋白功能丧失。

1.2 TM6SF2 rs58542926 E167K与脂质、肝酶变化的关系 GWAS及小鼠体内的研究[9-12]表明TM6SF2 rs58542926 E167K单核苷酸多样性通过影响肝内富甘油三酯脂蛋白(TG-rich lipoproteins，TRLs)及脂质小滴含量而影响肝脂肪代谢，使肝内甘油三酯含量(hepatic triglyceride content，HTGC)升高，而血脂(TG、LDL)含量降低；此外，抑制TM6SF2表达还会减少一些在TG合成起重要作用的基因(如PNPLA3、ACSS2、DGAT1及DGAT2)的表达，增大肝内脂滴的范围[12]。这使TM6SF2与各种肝病及心血管疾病[13-14]的发生具有一定的相关性。

TM6SF2 rs58542926 E167K可引起血浆丙氨酸氨基转移酶(alanine aminotransferase,ALT)含量显著升高(P=0.003)，突变纯合子(KK)有引起血浆天冬氨酸氨基转移酶(aspartate transaminase,AST)升高的趋势，可引起血浆碱性磷酸酶(alkaline phosphatase, ALP)显著下降，而与谷氨酰转肽酶(gamma glutamyl transpeptidase,GGT)的相关性并未得到[7]。研究[15]显示rs58542926多样性与NAFLD患者ALT(P=3.2×10-6)及AST(P=0.007)水平明显相关，相比于C等位基因(EE)携带者T等位基因(EK+KK)携带PNPLA3 rs738409 G者转氨酶水平明显升高(ALT：9.8%；AST：5%)，但明显低于对肝酶学变化的影响(ALT：28%)，慢性肝病患者中并未观察到这种相关性。

2 TM6SF2 rs58542926 E167K与肝脂肪化及NAFLD相关性研究

NAFLD为一种代谢综合征在肝内的表现，是一种进行性的肝脏疾病，以HTGC升高为特征，包括肝脂肪变性、NASH及肝纤维化，一些NAFLD甚至进展为肝硬化或HCC[16]。

早期研究[17-18]发现与TM6SF2连锁不平衡的基因NCAN(rs2228603 C>T)SNPs与HTGC及NAFLD明显相关，而Kozlitina等[7]研究表明TM6SF2 rs58542926 E167K SNPs导致HTGC升高而非NCAN,且首次提出TM6SF2与NAFLD有关。之后的研究表明TM6SF2 rs58542926 E167K SNPs使其表达蛋白减少，致使极低密度脂蛋白(very low-density lipoprotein,VLDL)含量降低导致HTGC升高，并导致肝脏脂肪变性(OR=1.379，95%CI：1.019～1.865，P=0.037)[16]，最终导致NAFLD的发生[19]。TM6SF2 rs58542926 E167K与NAFLD的相关性已被很多相关研究[19-21]证实，而两项分别基于日本人及中国人的研究[22-23]显示TM6SF2 rs58542926 E167K SNPs与NAFLD无相关性，考虑与样本量小及选择偏倚的存在等因素有关。

3 TM6SF2基因与肝纤维化及肝硬化易感性的关系

3.1 TM6SF2基因与肝纤维化的关系 Liu等[16]及Sookoian等[20]研究发现TM6SF2 rs58542926与NAFLD患者肝纤维化程度有关(β=0.549±0.135，95%CI：0.285～0.813，P<0.01)，是NAFLD相关性肝纤维化的独立影响因素(β=0.357±0.079，95%CI：0.203～0.511，P<0.01)；按纤维化程度不同等级分析，发现TM6SF2 rs58542926 C>T次等位基因明显增加晚期肝纤维化的风险。Dongiovanni等[24]认为TM6SF2致肝纤维化是由于肝内脂肪沉积而非致纤维化作用导致的。

一项Meta分析[25]显示，TM6SF2突变型个体血脂含量水平较低，考虑是由于脂质不能被肝脏分泌沉积于肝脏的原因，这也对肝脏造成损伤，进而发展为肝纤维化。研究显示T的携带者(EK+KK的个体)发生严重肝纤维化的风险大于C的纯合子(EE)，TM6SF2 rs58542926基因位点多态性与肝纤维化严重程度相关(OR=1.491，95%CI：1.131～1.851，P<0.0001)。

3.2 TM6SF2基因与肝硬化易感性的关系 Falleti等[26]研究将受试对象分为病毒性肝硬化、酒精性肝硬化及对照组，结果显示病毒性肝硬化组与对照组TM6SF2 rs58542926次等位基因频率无明显差异，而酒精性肝硬化组与对照组基因频率具有明显差异。说明TM6SF2 rs58542926与酒精性肝硬化可能存在一定的相关性，而具体关系及机制还需TM6SF2 rs58542926(T)更多研究证实。

4 TM6SF2基因与HCC易感性的关系

4.1 TM6SF2基因与NAFLD相关性HCC易感性的关系 Liu等[16]研究显示TM6SF2 rs58542926次等位基因与NAFLD相关性HCC发病相关(OR=1.922，95%CI：1.31～2.81，P<0.01)。但当与其他危险因素一起分析时，差异无统计学意义(P=0.42)，考虑可能与样本量小、基因频率低等有关。

4.2 TM6SF2基因与肝硬化恶变HCC的关系 Falleti等[26]研究了PNPLA3及TM6SF2与HCC的关系，研究纳入了511例肝硬化的患者做回顾性调查。研究显示与HCC的发生相关(OR=1.66，95%CI：1.01～2.74，P=0.043)，而与病毒相关性HCC的发生差异无统计学意义。两种基因在HCC的作用中没有相互作用。TM6SF2 rs58542926 T等位基因被称为HCC的高风险基因型(high risk genotypes，HGR)，C等位基因被称为低风险基因型(low risk genotypes，LGR)，TM6SF2 rs58542926 T/*基因型在HCC患者中的比例高于非HCC患者(OR=2.57，P=0.035)，HGR在乙肝、丙肝及酒精性肝硬化导致的HCC患者中频率依次升高，且与酒精性肝硬化相关HCC的发生具有明显相关性(P=0.0007)，而与病毒相关HCC的数据分析差异却无统计学意义，考虑与基因对脂质的调节作用有关。

总之，TM6SF2 rs58542926 E167K的作用至今仍未完全明确，逐渐有研究证明其与肝硬化、HCC的相关性。但TM6SF2 rs58542926 E167K如何介导HCC、肝硬化的具体机制仍需研究，与不同类型的肝硬化、HCC发生的关系还需更多研究证实。而TM6SF2 rs58542926次等位基因T纯合子基因频率低(<1%)，尚需更多的研究充分证实基因的影响。

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The relationship between TM6SF2 rs58542926 E167K single nucleotide polymorphisms and the susceptibility of liver cirrhosis and hepatocellular carcinoma

BING Hao, SHEN Jianhua, LI Yiling

Department of Gastroenterology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China

The transmembrane 6 superfamily member 2 (TM6SF2) is located on chromosome 19, mainly expressed in the intestine and liver, involved in lipid metabolism. The genic mutation of rs58542926 decreases the protein expression. Studies show that TM6SF2 rs58542926 E167K single nucleotide polymorphisms are associated with levels of liver fat, plasma liver enzyme levels and fibrosis severity, which are independent risk factors for nonalcoholic fatty liver disease (NAFLD). Recent studies find that TM6SF2 rs58542926 E167K single nucleotide polymorphisms are also associated with liver cirrhosis and hepatocellular carcinoma.

Liver cirrhosis; Hepatocellular carcinoma; TM6SF2 rs58542926 E167K; Susceptibility

国家自然科学基金(81570519)

邴浩，硕士研究生,研究方向：非酒精性脂肪性肝病的相关基因学研究。E-mail：2247725858@qq.com

李异玲，博士，主任医师，教授，研究方向：非酒精性脂肪性肝病的相关基因学研究。E-mail：lyl-72@163.com

10.3969/j.issn.1006-5709.2017.04.003

R735.7；R575.2

A

1006-5709(2017)04-0369-03

2016-09-12