Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
J Hepatol. 2012 Apr;56(4):758-64. doi: 10.1016/j.jhep.2011.10.019. Epub 2011 Dec 13.
BACKGROUND & AIMS: CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigated whether the CXCL1 rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis.
The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The CXCL1 rs4074 polymorphism was determined by a LightSNiP assay on the LightCycler system. CXCL1 serum levels and induction in response to HCV proteins were studied by ELISA.
Distributions of CXCL1 genotypes (GG/GA/AA) matched the Hardy-Weinberg equilibrium in all subgroups (HCV-associated cirrhosis: 29.3%/54.7%/16.0%; non-cirrhotic HCV infection: 45.1%/44.4%/10.5%, healthy controls: 46.2%/40.9%/12.9%). HCV-infected cirrhotic patients had a significantly greater CXCL1 rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR=1.573, p=0.03) and healthy controls (33.3%, OR=1.529, p=0.02). In vitro carriers of the A allele produced greater amounts of CXCL1 in response to TLR2-ligands including HCV core and NS3, and HCV-infected carriers of the CXCL1 rs4074 A allele had higher CXCL1 serum levels than those with the G/G genotype. Moreover, multivariate Cox-regression analysis confirmed age and the presence of a CXCL1 rs4074 A allele as risk factors for cirrhosis.
Enhanced production of CXCL1 in response to HCV antigens in carriers of the rs4074 A allele together with its increased frequency in cirrhotic patients with hepatitis C suggest the CXCL1 rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C.
趋化因子 CXCL1 是表达于肝星状细胞（HSC）的 CXC 趋化因子受体 2 的配体。因此，CXCL1 可能有助于 HSC 的激活和纤维化形成。在此，我们研究了 CXCL1 rs4074 多态性是否影响慢性丙型肝炎病毒（HCV）感染向肝硬化进展过程中 CXCL1 的表达。
该研究纳入了 237 例慢性 HCV 基因 1 型感染患者（75 例伴有肝硬化）和 342 例健康对照者。采用 LightCycler 系统上的 LightSNiP 检测法测定 CXCL1 rs4074 多态性。通过 ELISA 检测血清 CXCL1 水平及对 HCV 蛋白的诱导情况。
在所有亚组中（HCV 相关性肝硬化：29.3%/54.7%/16.0%；非肝硬化性 HCV 感染：45.1%/44.4%/10.5%，健康对照者：46.2%/40.9%/12.9%），CXCL1 基因型（GG/GA/AA）的分布均符合 Hardy-Weinberg 平衡。与无肝硬化的 HCV 感染患者（32.7%，OR=1.573，p=0.03）和健康对照者（33.3%，OR=1.529，p=0.02）相比，HCV 感染的肝硬化患者 CXCL1 rs4074 A 等位基因频率显著更高（43.3%）。体外携带 A 等位基因的个体对包括 HCV 核心和 NS3 在内的 TLR2 配体产生更多的 CXCL1，且携带 CXCL1 rs4074 A 等位基因的 HCV 感染者的 CXCL1 血清水平高于 G/G 基因型携带者。此外，多变量 Cox 回归分析证实年龄和 CXCL1 rs4074 A 等位基因的存在是肝硬化的危险因素。
在携带 rs4074 A 等位基因的个体中，对 HCV 抗原的反应性产生更多的 CXCL1，以及该等位基因在丙型肝炎肝硬化患者中的高频率，提示 CXCL1 rs4074 A 等位基因是丙型肝炎肝硬化进展的遗传危险因素。
