跨膜 6 超家族成员 2 基因 E167K 变异影响慢性丙型肝炎患者的脂肪变性和肝损伤。

Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients.

机构信息

Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

出版信息

Hepatology. 2015 Jul;62(1):111-7. doi: 10.1002/hep.27811. Epub 2015 May 6.

DOI:10.1002/hep.27811

PMID:25820484

Abstract

UNLABELLED

Steatosis and inherited host factors influence liver damage progression in chronic hepatitis C (CHC). The transmembrane 6 superfamily member 2 (TM6SF2) gene E167K variant increases liver fat and risk of progressive steatohepatitis by interfering with lipoprotein secretion. Our aim was to determine whether the E167K variant affects histological severity of steatosis, necroinflammation, and fibrosis in a cross-sectional cohort of 815 Italian therapy-naïve CHC patients. The association with clinically significant fibrosis was replicated in 645 Swiss/German patients. The TM6SF2 E167K variant was genotyped by TaqMan assays, steatosis graded according to the nonalcoholic fatty liver disease activity score, and necroinflammation and fibrosis graded and staged according to Ishak in Italian, and to Metavir in Swiss/German patients. The E167K variant was detected in 69 (9%) Italian patients and was associated with more severe steatosis, independently of confounders (P = 0.038). The association between E167K and steatosis severity was present in patients not infected by genotype 3 (G3) HCV (P = 0.031), but not in those infected by G3 HCV (P = 0.58). Furthermore, the E167K variant was associated with more severe necroinflammation (Ishak grade; adjusted P = 0.037) and nearly associated with more severe fibrosis (Ishak stage; adjusted P = 0.058). At multivariate logistic regression analysis, the E167K variant was independently associated with histologically probable or definite cirrhosis (Ishak stage S6; odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.18-3.93; P = 0.010). After further conditioning for steatosis and necroinflammation, the E167K variant remained associated with cirrhosis (OR, 3.15; 95% CI: 1.60-5.99; P < 0.001). In Swiss/German patients, the E167K variant was independently associated with clinically significant fibrosis Metavir stage F2-F4 (OR, 1.81; 95% CI: 1.12-3.02; P = 0.016).

CONCLUSION

TM6SF2 E167K variant impacts on steatosis severity and is associated with liver damage and fibrosis in patients with CHC.

摘要

目的

研究跨越大肠杆菌科患者 815 例意大利未接受治疗的慢性丙型肝炎（CHC）患者的 TM6SF2 基因 E167K 变体是否影响脂肪变性、坏死性炎症和纤维化的组织学严重程度。

方法

采用 TaqMan 法检测 TM6SF2 E167K 变体，根据非酒精性脂肪性肝病活动评分（Nonalcoholic fatty liver disease activity score）对脂肪变性进行分级，根据 Ishak 在意大利和 Metavir 在瑞士/德国患者中的标准对坏死性炎症和纤维化进行分级和分期。

结果

在 69 例（9%）意大利患者中检测到 E167K 变体，E167K 变体与更严重的脂肪变性独立相关（P=0.038）。E167K 与脂肪变性严重程度的相关性在未感染基因型 3（G3）HCV 的患者中存在（P=0.031），但在感染 G3 HCV 的患者中不存在（P=0.58）。此外，E167K 变体与更严重的坏死性炎症（Ishak 分级；调整后的 P=0.037）和纤维化（Ishak 分期；调整后的 P=0.058）有关。多变量逻辑回归分析显示，E167K 变体与组织学上可能或确定的肝硬化（Ishak 分期 S6；比值比[OR]：2.19；95%置信区间[CI]：1.18-3.93；P=0.010）独立相关。在进一步为脂肪变性和坏死性炎症调整后，E167K 变体仍与肝硬化相关（OR，3.15；95%CI：1.60-5.99；P<0.001）。在瑞士/德国患者中，E167K 变体与临床显著纤维化 Metavir 分期 F2-F4 独立相关（OR，1.81；95%CI：1.12-3.02；P=0.016）。