The CXCL1 rs4074 A allele is associated with enhanced CXCL1 responses to TLR2 ligands and predisposes to cirrhosis in HCV genotype 1-infected Caucasian patients

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• 作者：Hans Dieter Nischalke¹ ; Cordula Berger¹ ; Carolin Luda¹ ; Tobias M&uuml ; ller² ; Thomas Berg³ ; Martin Coenen¹ ; Benjamin Kr&auml ; mer¹ ; Christian K&ouml ; rner¹ ; Jonel Trebicka¹ ; Frank Gr&uuml ; nhage⁴ ; Frank Lammert⁴ ; Jacob Nattermann¹ ; Tilman Sauerbruch¹ ; Ulrich Spengler¹ ; ^{ulrich.spengler@ukb.uni-bonn.de}
• 关键词：CXCL1 ; CXC chemokine-ligand-1 ; HCV ; hepatitis C virus ; TLR ; Toll-like receptor ; ELISA ; enzyme-linked immunosorbent assay ; NS3 ; non-structural protein 3 ; PBS ; phosphate buffered saline ; OR ; odds ratio ; CI ; confidence interval
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：April, 2012
• 卷：56
• 期：4
• 页码：758-764
• 文件大小：717 K

摘要

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class="h4">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 m>CXCL1m> rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis.

class="h4">Methods

The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The m>CXCL1m> 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.

class="h4">Results

Distributions of m>CXCL1m> 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 m>CXCL1m> rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR = 1.573, m>p m>= 0.03) and healthy controls (33.3%, OR = 1.529, m>p m>= 0.02). m>In vitrom> 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 m>CXCL1m> 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 m>CXCL1m> rs4074 A allele as risk factors for cirrhosis.

class="h4">Conclusions

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 m>CXCL1m> rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C.