Elsevier

Gene

Volume 557, Issue 2, 25 February 2015, Pages 158-162
Gene

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

https://doi.org/10.1016/j.gene.2014.12.025Get rights and content

Highlights

  • Interleukin-6 (IL-6) and its related cytokines play important roles in the liver.

  • Polymorphisms in the promoter of cytokine genes were related to serum AST and ALT.

  • An IL6 polymorphism (C-634G, rs1800796) was associated with serum AST levels.

  • Associations of this polymorphism with serum AST and ALT were marked in males.

Abstract

Cytokines, including interleukin-6 (IL-6), play an important role in the liver. The aim of this study was to investigate associations between common polymorphisms in potential functional promoters of cytokine genes and liver damage markers among enrollees of a large Japanese cohort study. Subjects included 3257 Japanese individuals (1608 men and 1649 women, aged 35–69 years). Six single nucleotide polymorphisms (SNPs) in the promoter regions of five cytokine genes, IL1B (T-31C), IL6 (C-634G), IL8 (T-251A), IL10 (T-819C), tumor necrosis factor-A (TNFA) (T-1031C), and TNFA (C-857T), were genotyped by polymerase chain reaction. Information regarding alcohol intake, smoking habits, height, and weight was collected by a self-administered questionnaire. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured during a routine health check-up. Of the six SNPs genotyped, an IL6 polymorphism (rs1800796, C-634G) was most strongly associated with a liver damage marker, AST. Mean serum AST was significantly different among the three genotypes (mean ± SD, 22.7 ± 7.3 IU/L for CC, 22.8 ± 7.7 IU/L for CG, and 24.3 ± 8.6 IU/L for GG, p = 0.011 by analysis of variance). The differences remained significant after adjustment for potential confounders by general linear models. The variations in mean serum AST and ALT levels were marked especially among men. Thus, the functional polymorphism IL6 C-634G may affect serum AST and ALT levels, possibly through different IL-6 production.

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

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