Elsevier

Cytokine

Volume 39, Issue 2, August 2007, Pages 116-122
Cytokine

Influence of the IL-6 −572C > G polymorphism on inflammatory markers according to cigarette smoking in Korean healthy men

https://doi.org/10.1016/j.cyto.2007.06.005Get rights and content

Abstract

We investigated whether smoking would interact with the interleukin-6 (IL-6) polymorphisms (−174G > C and −572C > G, −597G > A and −1363G > T) in determining circulating levels of inflammatory markers and its consequence to oxidative stress. The G/G genotype (n = 26) of the −572C > G in nonsmokers (n = 376) was associated with higher IL-6 (P = 0.028), fibrinogen (P = 0.007) and ox-LDL (P = 0.006) than those with C/C (n = 209) or C/G (n = 141). Results were similar for nonsmokers and smokers (n = 268), but in smokers, the −572G/G genotype was associated with a greater difference in levels of IL-6 (P = 0.031), fibrinogen (P = 0.001), ox-LDL (P = 0.037) and PGF (P = 0.050). IL-6 had positive relations with CRP, fibrinogen, ox-LDL and PGF. There was no evidence of an effect of −572C > G genotype on CRP levels in nonsmokers, however, this polymorphism was associated with a highly significant effect on CRP in smokers (P < 0.001) (genotype-smoking interaction P = 0.04, adjusted for age, BMI and IL-6). The C allele frequency at the −174 promoter region of IL-6 was very rare (<0.01) and −597G > A and −1363G > T were monomorphic in this study. Our results suggest that IL-6 −572C > G has a greater response over time to the inflammatory effects of smoking and this may result in smokers having higher oxidative stress in subjects with G/G compared to C/C or C/G.

Introduction

Interleukin-6 (IL-6), a pleiotropic, proinflammatory cytokine, seems to play an important role in the pathogenesis of cardiovascular disease [1]. IL-6 is produced by a variety of cells including macrophages after stimulation such as infection, trauma, or undergoing inflammatory activation in the vessel wall [2], [3]. However, increased IL-6 production may occur in the absence of infections [4]. Smoking status, the established cardiovascular risk factors, is known to be associated with increased levels of systemic markers of inflammation, such as acute-phase proteins, IL-6, C-reactive protein (CRP) and fibrinogen [5], [6]. Interestingly, only some people exposed to cigarette smoke develop cardiovascular disease (CVD), indicating that genetic factors are important determinants of susceptibility [7] Thus, genetic polymorphisms that determine the rate of acute-phase protein production would be important genetic risk factors for atherosclerosis [8].

In vitro study showed that polymorphisms at positions −174 and −572 (−634) in the IL-6 gene affect transcriptional strength [9], [10] which are functionally important. However, previous population genetic studies are inconclusive regarding associations between these polymorphisms and circulating IL-6 levels [8], [11], [12], [13], [14], [15], but the reasons for the discrepancies among studies are unclear. Furthermore, allele frequencies at −572 are quite different from Japanese and another Korean (C > G, G: 0.249) [15], [16], [17], [18] to Caucasian population (G > C, C: 0.04–0.06) [19].

Therefore, we determined the genotype effects of IL-6 promoter polymorphisms on circulating levels of IL-6 in healthy Korean men who have different allele frequencies of IL-6 promoter polymorphisms from Caucasian. We also investigated whether smoking would interact with IL-6 promoter polymorphisms in determining circulating levels of inflammatory markers and its consequence to oxidative stress such as lipoprotein oxidation and lipid peroxidation.

Section snippets

Study subjects

Healthy male subjects (n = 644) were recruited concomitantly from participants in prospective human genetic study, supported by a Genome Research Development Project on Health and Medicine (Project No. A000385), Ministry of Health and Welfare. The inclusion criteria were 38  age < 72 years, no history or diagnosis of CVD, diabetes mellitus, cancer (clinically or by anamnesis) or renal disease and no pathological electrocardiogram patterns. None of the subjects were taking medication. Written informed

Main characteristics of the study subjects

Table 1 presents the main characteristics of the study population, which included 268 smokers with an average consumption of 18 ± 1 cigarettes/day. There were no significant differences between smokers and nonsmokers (n = 376) in age, BMI, waist–hip ratio (WHR), blood pressure, serum glucose, insulin, HOMA-IR, lipid profiles and alcohol intake. However, smokers had a trend toward higher concentrations of IL-6 (P = 0.143), fibrinogen (P = 0.069) and PGF (P = 0.060) compared to nonsmokers. Ox-LDL

Discussion

In this study, we observed associations between IL-6 −572C > G promoter polymorphism and circulating levels of IL-6. The −572 G/G genotype (6.8%) was associated with significantly higher circulating levels of IL-6 than the C/C or C/G genotype. Especially, an absolute difference in the mean estimates of IL-6 between the G/G and G/C or C/C genotypes in smokers was greater as compared to nonsmokers. This might indicate that the higher IL-6 concentration in smokers support the exaggeration of the G/G

Acknowledgments

This study was partly supported by (1) Ministry of Science and Technology, Seoul, Korea (M10642120002-06N4212-00210); (2) National Research Laboratory Project No. R0A-2005-000-10144-0, Ministry of Science and Technology, Seoul, Korea; (3) Korea Health 21 R&D Projects, Ministry of Health and Welfare, Seoul, Korea (A000385, A050376).

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    These authors equally contributed to this work.

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