A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.
OBJECTIVE
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.
D000328:Adult; D018932:Chemokine CCL2 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000276:immunology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012720:Severity of Illness Index
D018932:Chemokine CCL2