Gastroenterology

Gastroenterology

Volume 125, Issue 4, October 2003, Pages 1085-1093
Gastroenterology

Clinical-liver,pancreas, and biliary tract
A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease

https://doi.org/10.1016/S0016-5085(03)01213-7Get rights and content

Abstract

Background & Aims: Factors influencing the progression of chronic hepatitis C virus (HCV) infection are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, and its hepatic expression is up-regulated during chronic HCV infection mainly in activated hepatic stellate cells (HSC). In this study, we investigated the correlation of the functional −2518 MCP-1 promoter polymorphism with hepatic MCP-1 expression and the disease outcome in patients with HCV. Methods: MCP-1 genotyping was performed in 206 patients and 139 healthy controls. Hepatic MCP-1 messenger RNA (mRNA) expression was quantified by real-time PCR in 58 HCV patients. Cytokine-induced MCP-1 secretion of activated human HSC (n = 13) was determined by enzyme-linked immunosorbent assay (ELISA). Mobility-shift assays were performed using probes corresponding to the MCP-1 promoter sequence (−2511 to −2528) with or without the A to G mutation at −2518. Results: Frequency of MCP-1 genotypes did not differ between HCV patients and controls. However, carriers of the G allele were significantly more frequent in HCV patients with more advanced fibrosis and severe inflammation. In accordance, hepatic MCP-1 mRNA levels were significantly higher in patients with more advanced fibrosis and in patients carrying the G allele. Furthermore, cytokine-induced MCP-1 secretion of HSC isolated from carriers of the G allele was significantly higher, and there was binding activity in nuclear extracts from activated HSC specifically to the G allele, providing a potential mechanism for the differences seen. Conclusions: Inheritance of the −2518 MCP-1 G allele, which appears to affect hepatic MCP-1 expression, may predispose HCV patients to more severe hepatic inflammation and fibrosis.

Section snippets

Patients and controls

We studied retrospectively 206 patients (135 male, 71 female; mean age: 38.1 ± 13.0 years) with chronic hepatitis C (positive for HCV-RNA and anti-HCV) consecutively admitted to the hospital of the University of Regensburg. All patients were negative for hepatitis B surface antigen or antibodies to human immunodeficiency virus, and none of them had evidence of other types of liver disease. Risk factors for acquisition of hepatitis C infection were previous intravenous drug abuse in 28.2% of

Frequency of the −2518 MCP-1 polymorphism in patients with chronic HCV infection

The frequencies of the different MCP-1 genotypes A/A homozygotes, A/G heterozygotes, and G/G homozygotes are summarized in Table 1, revealing no significant differences between 206 patients with chronic hepatitis C infection and 139 healthy controls. Frequencies of individual genotypes were similar to those previously reported in other white control populations.15, 17, 19, 20

Because most previous in vitro and epidemiologic studies reported functional and disease-related differences mainly

Discussion

The results of this study demonstrate an association between different MCP-1 genotypes and hepatic fibrosis and inflammation in patients with chronic hepatitis C, confirming the initial hypothesis that host genetic factors may account for some of the variability in the rate of disease progression seen in these patients. This relationship between MCP-1 genotypes and hepatic fibrosis and inflammation is in accordance with the well-documented role of MCP-1 in the pathophysiology of chronic liver

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    Supported by grants from the Deutsche Forschungsgemeinschaft (DFG; to A.B. and C.H.) and by the Else Kröner Fresenius-Stiftung (to C.H. and H.H.).

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