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Introduction
Alcoholism is a major cause of chronic liver disease worldwide [1] and contributes up to 48% of cirrhosis-related deaths in the United States [2]. The spectrum of alcohol-related liver injury ranges from simple fatty liver to more severe forms of liver damage such as liver fibrosis and cirrhosis, and even superimposed with hepatocellular carcinoma.
More than 95% of heavy drinkers develop a fatty liver, but only up to 35% of these individuals develop more severe forms of alcoholic liver disease [3]. This indicates that other factors may be involved. Several risk factors for alcoholic liver disease have been identified: sex, obesity, drinking patterns, dietary factors, genetic factors, and cigarette smoking [4–6]. Factors such as female gender, obesity, and drinking patterns have been well documented [7,8]. Genetic factors may also influence susceptibility to advanced alcoholic liver disease; however, only scanty data are available on this topic.
The mechanism of alcohol liver damage initiates from the activation of innate immunity in the sinusoid by endotoxins such as lipopolysaccharides from portal circulation. The toxin is produced by Gram-negative bacteria in the intestine and translocates to portal circulation owing to increased intestinal permeability after excess alcohol consumption [9]. This stimulation initiates and promotes oxidative stress and inflammatory process via interaction with Kupffer cells in the sinusoid [10]. The proinflammatory cytokines released from Kupffer cells may further activate stellate cells and cause liver fibrosis. Therefore, inflammatory responses originating from Kupffer cells may play an important role in the process of alcoholic liver cirrhosis [11]. Hence, the different inflammatory responses of immune cells and following cytokine expression in the liver may be critical to the pathogenesis of alcoholic liver cirrhosis.
Therefore, we postulate that the gene expression of these cytokines of the Kupffer cells may be responsible for the immune response and subsequent fibrosis. Because the major cytokines secreted by Kupffer cell are TNFα, IL 1, IL 6, IL 10, PDGF, MCP 1, and TGF-β [10,11], we selected four cytokines with reported promoter polymorphisms for further genotyping. In this study, we evaluated the association of promoter polymorphisms on IL 10: –1082 G>A (rs1800896), –819 C>T (rs180871), –592 C>A (rs1800872), IL 6: –572 G>C (rs1800796), IL 1β: –511 T>C (rs 1143627), as well as TNFα:...