Atherosclerosis 207 (2009) 466–470 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Interleukin-6 promoter polymorphism and cardiovascular risk factors: The Health 2000 Survey Antti Riikola a , Kalle Sipilä b , Mika Kähönen a,b , Antti Jula c , Markku S. Nieminen d , Leena Moilanen e , Y. Antero Kesäniemi f , Terho Lehtimäki a,g , Janne Hulkkonen b,∗ a The Medical School at the University of Tampere, Tampere, Finland b Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland c Department of Health and Functional Capacity, National Public Health Institute, Helsinki, Finland d Department of Medicine, University of Helsinki, Helsinki, Finland e Department of Medicine, Kuopio University Hospital, Kuopio, Finland f Department of Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland g Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University Hospital, Finland article info Article history: Received 18 January 2009 Received in revised form 1 June 2009 Accepted 2 June 2009 Available online 11 June 2009 Keywords: Interleukin-6 Polymorphism Genetics Cytokine Atherosclerosis abstract Objective: Inflammatory factors modify the risk of cardiovascular diseases and atherosclerosis. The single base genetic polymorphism in the promoter region of inflammatory cytokine interleukin-6 (IL6 -174 G>C, rs1800795) is associated with the variation of IL-6 production. The aim of this study was to investigate whether IL6 -174 G>C is associated with the risk factors and early markers of atherosclerosis. Methods: As part of Finnish Health 2000 Study, we performed carotid artery ultrasound examinations, IL6 -174 G>C genotyping and cardiovascular risk factor determination for 1334 subjects aged 46–76 years. Results: In men, serum total cholesterol was higher in IL6 -174 GG (5.70 ± 0.88 mmol/L) than in the GC (5.51 ± 0.98 mmol/L) or CC (5.38 ± 0.97 mmol/L, mean ± SD, p = 0.0059) groups. The same order was seen in LDL-C (GG 3.64 ± 0.83 mmol/L, GC 3.41 ± 0.88 mmol/L, CC 3.30 ± 0.91 mmol/L, p = 0.0017). The opposite association was observed with plasma fasting glucose levels (GG 5.93 ± 0.97, GC 6.11 ± 1.34, CC 6.34 ± 1.59 mmol/L, p = 0.043) and BMI (GG 26.8 ± 3.42, GC 27.5 ± 4.32, CC 28.0 ± 3.81 kg/m 2 , p = 0.027). IL6 -174 allele C homozygous men indicated a trend towards higher systolic blood pressure. IL6 -174 G>C was not associated with carotid artery compliance, intima media thickness or CRP. The effect size of IL6 -174 G>C on cardiovascular risk factors was not significant in women. These results suggest that IL6 -174 G>C modifies the levels of several metabolic risk factors of atherosclerosis in men. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Inflammation plays a key role in pathogenesis of atherosclero- sis [1]. Interleukin-6 (IL-6) is a pleiotropic inflammatory cytokine which has been associated with atherosclerosis and cardiovascu- lar disease [2,3]. A single G>C base exchange polymorphism in the promoter region of the IL-6 gene (IL6 -174 G>C) is associated with IL-6 production. In the initial studies IL6 -174 allele G homozygous and G/C heterozygous subjects have shown a higher expression of IL-6 protein, higher transcriptional activity and higher inducible IL- 6 responses than subjects homozygous for IL6 allele C [4–6]. The effect of IL6 -174 G>C on circulating IL-6 is more complex and may be dependent on the presence of immune challenge, age and BMI of subjects as well as physiological and psychosocial stress and various ∗ Corresponding author at: Tampere University Hospital, Department of Clinical Physiology, P.O. Box 2000, FI-33521 Tampere, Finland. Tel.: +358 3 311 67760; fax: +358 3 311 64329. E-mail address: janne.hulkkonen@uta.fi (J. Hulkkonen). metabolic factors [7,8]. IL6 -174 G>C has been associated with the risk of ischemic cerebrovascular events [9] and coronary heart dis- ease in men [10,11]. The frequency of IL6 allele C seems to decrease among old people, suggesting an association with mortality [12,13]. Allele C has also been associated with high blood pressure [11,14] and high levels of C-reactive protein [11,15]. A recent joint analysis conducted on the basis of data from 17 studies suggested associa- tion of IL-6 G>C with fasting glucose levels independently of BMI [7]. Established cardiovascular risk factors such as serum choles- terol, blood pressure, obesity and smoking are associated with increased arterial stiffness [16]. Ultrasonographically measured carotid artery compliance and common carotid intima media thick- ness (IMT) are markers of early atherosclerosis [17–19]. IL6 -174 G>C genotypes have been associated with carotid artery compliance and carotid IMT [14,20]. In spite of intensive research, the role of IL6 -174 G>C as a risk factor for cardiovascular diseases has remained inconsistent [15,21], and several authors have expressed a need for further studies [11,14,21,22]. We have previously found that IL-6 G>C 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.06.004