Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5' and 3' flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC.

Correlation analysis between an IL-6 genetic polymorphism and non-small cell lung cancer prognosis

“…IL-6 is highly expressed in lung, brain, and liver tissues, and it promotes tumor metastasis by leading tumor cells into the peripheral circulation to enter in other organs (Culig et al, 2005). In recent years, it has been confirmed that IL-6 and IL-8 may recruit circulating tumor cells back to the original tumor location, which is known as "tumor self-cultivation", and this can accelerate tumor growth, neovascularization, and stromal cell recruitment (Hefler et al, 2003;Zhang et al, 2009;Giannitrapani et al, 2013). Many studies have also suggested that high serum IL-6 levels are related to poor prognosis in breast, prostate, pancreatic, and ovarian cancers.…”

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…IL-6 is another cytokine that involved in the regulation of several cellular processes and has been demonstrated to be associated with NASH in several ethic cohorts [141,145] . However, the polymorphism of G/C allele is questionable.…”

“…Christou et al [88] 2012 RBP4 has the ability to induce insulin resistance in the adipose tissue Circulating RBP4 can be influenced by nonmetabolic conditions and interventions to associate with insulin resistance [145] . Hence, insulin resistance and augmentation of hepatic inflammation could be modulated by other factors than TNF-α and IL-6.…”

Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease

“…However, its possible role in NAFLD has not been fully studied. Currently, the presence of the GG genotype was observed to be in high frequency in HCV-related chronic hepatitis, liver cirrhosis and HCC (79). The variant predisposes to produce higher levels of IL-6 that contributes to the progression of HCC.…”