Associations between polymorphisms of interleukin-6 and related cytokine genes and serum liver damage markers: a cross-sectional study in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study
Introduction
Cytokines are secretory proteins that function as mediators in immune and inflammatory reactions. The increased secretion of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, increases risk of disease such as lung disease (Bai et al., 2013, Kiyohara et al., 2014) and hepatocellular carcinoma (Jin et al., 2011). Serum levels of cytokines are regulated at the transcriptional level. Previous clinical studies (Yin et al., 2013) showed that several polymorphisms in IL promoter regions, such as IL6 (C-634G, rs1800796), IL8 (T-251A, rs4073), and IL10 (T-819C, rs1800871), were associated with IL gene transcription and secretion. IL-6 functions in both natural and adaptive immunity, playing an important role in blood formation and inflammatory reactions (Heinrich et al., 1990, Sun et al., 2004). In the liver, it induces an inflammatory reaction and causes hepatocyte death. In the subsequent regeneration process, gene abnormalities are accumulated, which may result in hepatocellular carcinoma (Giannitrapani et al., 2013, Streetz et al., 2000). Moreover, IL-6 stimulates the synthesis of C-reactive protein (CRP) by hepatocytes (Chen et al., 2013, Jang et al., 2012). IL-6 signals through pathways such as PI3K, JAK/STAT, p38 MAP kinase, and AP-1/JNK to mediate angiogenesis, cell proliferation, and inhibition of apoptosis that can lead to liver cirrhosis and cancer (Johnson et al., 2012).
Previous studies investigated functions of other cytokines related to IL-6 in the liver. When the inflammation of the liver becomes chronic owing to hepatitis virus, alcohol drinking, or obesity, nuclear factor-kappa B (NF-кB) is activated and it induces inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Because TNF-α and IL-1β also induce IL-6, the production of IL-6 is further enhanced (Johnson et al., 2012).
There have been several reports on associations between IL6 C-634G polymorphisms and chronic inflammation or disease. Saijo et al. (2007) reported that the IL6-634G allele was significantly associated with higher CRP level in nonsmokers. Lim et al. (2011) showed that carriers of the G allele had a higher risk of lung cancer than non-carriers. From these studies, the IL6-634G allele is considered a risk factor for several diseases. However, few studies have shown associations between the IL6-634G allele and serum liver damage markers such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
This study, therefore, aimed to explore the associations of polymorphisms of IL6 and related cytokine genes with serum liver damage markers in a large Japanese population.
Section snippets
Study subjects
Subjects were participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Details of the J-MICC Study have been described elsewhere (Hamajima and J-MICC Study Group, 2007, Wakai et al., 2011). Briefly, the J-MICC participants for the present analysis were those aged 35–69 years recruited from the Japanese population throughout Japan between 2004 and 2008 by 10 research teams. They provided venous blood and health examination data, as well as lifestyle and medical history
Results
The distribution of all genotypes was in Hardy–Weinberg equilibrium (p > 0.05 for all). Table 1 shows serum levels of AST and ALT by genotype of the six polymorphisms of IL1B, IL6, IL8, IL10, and TNFA genes. The IL6 C-634G and IL10 T-819C genotypes were significantly associated with AST (p = 0.011 for IL6 and p = 0.048 for IL10). Because the IL6 C-634G polymorphism was most strongly associated with liver damage markers, we further focused on this polymorphism in the following analyses.
Discussion
In the current study, serum AST and ALT levels were higher in those with the GG genotype of IL6 C-634G polymorphism than in those with the CC genotype. Because previous studies showed that the -634G allele enhanced the production and secretion of IL-6 (Kitamura et al., 2002, Motoyama et al., 2012), the secretion of IL-6 may be promoted among those with the minor homozygous genotype, which might result in higher levels of liver damage markers through a mild inflammatory reaction.
In the smokers
Conclusions
IL6 C-634G polymorphism (rs1800796) was associated with a higher serum level of liver damage markers especially AST, and smoking and drinking habits might enhance the effect of the IL6-634G allele on liver damage. Further investigations are required to take into account the level of circulating IL-6 and the effect of other IL6 SNPs including G-174C (rs1800795) and their linkage disequilibrium with the IL6 C-634G polymorphism.
Acknowledgments
We thank Kyota Ashikawa, Tomomi Aoi, and other members of the Core for Genomic Medicine, Center for Integrative Medical Sciences, RIKEN for the support with genotyping in the study, Yoko Mitsuda, Keiko Shibata, and Etsuko Kimura at the Department of Preventive Medicine of Nagoya University Graduate School of Medicine, Miki Watanabe and Isao Oze at the Division of Epidemiology and Prevention of the Aichi Cancer Center Research Institute, Fusako Katsurada at the Department of Health Science of
References (29)
- et al.
Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6–174G/C polymorphism is associated with non-alcoholic steatohepatitis
Dig. Liver Dis.
(2009) - et al.
Impact of serum levels and gene polymorphism of cytokines on chronic hepatitis C infection
Transl. Res.
(2007) - et al.
Serum interleukin-6 and C-reactive protein as a prognostic indicator in hepatocellular carcinoma
Cytokine
(2012) - et al.
Genetic polymorphisms involved in the inflammatory response and lung cancer risk: a case–control study in Japan
Cytokine
(2014) - et al.
Interaction between interleukin-1 beta − 31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese
Cancer Lett.
(2008) - et al.
Lack of association between a functional polymorphism (rs1800796) in the interleukin-6 gene promoter and lung cancer
Diagn. Pathol.
(2014) - et al.
Genetic single-nucleotide polymorphisms of inflammation-related factors associated with risk of lung cancer
Med. Oncol.
(2013) - et al.
Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women
Arterioscler. Thromb. Vasc. Biol.
(2002) - et al.
Novel single nucleotide polymorphisms in interleukin 6 affect tacrolimus metabolism in liver transplant patients
PLoS One
(2013) - et al.
Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C
Immunogenetics
(2011)
Genetic association of interleukin-6 polymorphism (-174G/C) with chronic liver diseases and hepatocellular carcinoma
World J. Gastroenterol.
The Japan Multi-institutional Collaborative Cohort Study (J-MICC Study) to detect gene–environment interactions for cancer
Asian Pac. J. Cancer Prev.
Interleukin-6 and the acute phase response
Biochem. J.
Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review
J. Cancer Res. Clin. Oncol.
Cited by (11)
Berberine inhibits gastric cancer development and progression by regulating the JAK2/STAT3 pathway and downregulating IL-6
2022, Life SciencesCitation Excerpt :IL-6 is strongly associated with tumor development, and is often highly expressed in blood, tissues and cells of tumor patients [7,8]. The elevated expressions of IL-6 and abnormal signaling pathways can facilitate the growth and migration of common tumors, including breast cancer [9], liver cancer [10], and GC [11]. IL-6 signal transduction through a receptor complex coupled to IL-6 causes the phosphorylation of JAK2 to activate downstream signaling pathways [12].
Effectiveness of Soursop Leaf Extract (Annona muricata l.) on IL-6 Levels in Mammary Sprague dawley Female Rats Induced by Staphylococcus aureus
2020, Unnes Journal of Public HealthMeta-analysis of the role of IL-6 rs1800795 polymorphism in the susceptibility to prostate cancer
2017, Medicine (United States)