Association of Humoral Immunity to Human Hsp60 with the IL-6 Gene Polymorphism C-174G in Patients with Type 2 Diabetes and Controls

A. Mostafazadeh; C. Herder; B. Haastert; P. Hanifi-Moghaddam; N. Schloot; W. Koenig; T. Illig; B. Thorand; R. Holle; M.-B. Eslami; H. Kolb; for the KORA Group

doi:10.1055/s-2005-861209

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2005; 37(4): 257-263
DOI: 10.1055/s-2005-861209

Original Clinical

Association of Humoral Immunity to Human Hsp60 with the IL-6 Gene Polymorphism C-174G in Patients with Type 2 Diabetes and Controls

A. Mostafazadeh^* ^1, ² , C. Herder^* ¹ , B. Haastert³ , P. Hanifi-Moghaddam¹ , N. Schloot¹ , W. Koenig⁴ , T. Illig⁵ , B. Thorand⁵ , R. Holle⁶ , M.-B. Eslami⁷ , H. Kolb¹ , for the KORA Group^**

¹ German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich-Heine-University, Düsseldorf, Germany
² Department of Microbiology and Immunology, Babol University of Medical Sciences, Babol, Iran
³ Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at the Heinrich-Heine-University, Düsseldorf, Germany
⁴ Department Internal Medicine II-Cardiology, University of Ulm, Medical Center, Ulm, Germany
⁵ GSF National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany
⁶ GSF National Research Center for Environment and Health, Institute of Health Economics and Health Care Management, Neuherberg, Germany
⁷ Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
⁸* These authors contributed equally to this work.
⁹** The KORA Group consists of H.E. Wichmann (speaker), H. Löwel, C. Meisinger, T. Illig, R. Holle, J. John and their co-workers who are responsible for the design and conduct of the KORA studies.

Abstract

The relationship between humoral immunity to hsp60 and type 2 diabetes along with other relevant metabolic, inflammatory and immunogenetic variables was studied in 76 non-diabetic and 74 diabetic persons aged 55 - 74 years selected from the population-based KORA Survey 2000. Antibodies to human hsp60 were measured in serum samples by ELISA. Hsp60 antibodies were detected in all but two individuals in a considerable range of titres (22 - 1,856 AU/ml). There was no significant association to age and sex, or to key clinical or metabolic parameters (BMI, WHR, HbA_1c, total cholesterol, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure, albumin, uric acid) or immunological parameters (CRP, IL-6, sIL-6R, TNFα, sTNFαR60, sTNFαR80). Analysis of antibody-positive individuals revealed an association between hsp60 antibodies and diabetes at borderline significance (p = 0.047), which was lost when the two antibody-negative individuals were included. Genetic analyses indicated that this association was significant in carriers of the C allele of the IL-6 promoter region polymorphism at nucleotide -174 (p = 0.02), but not in GG genotype carriers. We conclude that humoral immunity to human hsp60 may be enhanced in those diabetic patients carrying the -174C allele of the IL-6 gene. This finding may contribute to an understanding of the relationship between the -174C allele and increased risk of atherosclerosis.

Key words

Heat shock protein 60 - Antibodies - Inflammation - Diabetes

Full Text

References

1 Hightower L E. Heat shock, stress proteins, chaperones and proteotoxicity. Cell. 1991; 66 191-197
2 Kaufmann S HE. Heat shock proteins and the immune response. Immunol Today. 1990; 11 129-136
3 Young R A. Stress proteins and immunology. Annu Rev Immunol. 1990; 8 401-420
4 Chen W, Syldath U, Bellmann K, Burkart V, Kolb H. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol. 1999; 162 3212-3219
5 Kol A, Bourcier T, Lichtman H, Libby P. Chlamydial and human heat shock protein 60 s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest. 1999; 103 571-577
6 Flohé S B, Brüggemann J, Lendemans S, Nikulina M, Meierhoff G, Flohé S, Kolb H. Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol. 2003; 170 2340-2348
7 Pickup J C, Crook M A. Is type II diabetes mellitus a disease of the innate immune system?. Diabetologia. 1998; 41 1241-1248
8 Pradhan A D, Manson J E, Rifai N, Buring J E, Ridker P M. C-reactive protein, interleukin-6, and risk of developing type 2 diabetes mellitus. JAMA. 2001; 286 327-334
9 Müller S, Martin S, Koenig W, Hanifi-Moghaddam P, Rathmann W, Haastert B, Giani G, Illig T, Thorand B, Kolb H. Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. Diabetologia. 2002; 45 805-812
10 Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S, Stulnig T, Luef G, Wick G. Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis. Lancet. 1993; 341 255-259
11 Burian K, Kis Z, Virok D, Endresz V, Prohaszka Z, Duba J, Berencsi K, Boda K, Horvath L, Romics L, Fust G, Gonczol E. Independent and joint effects of antibodies to human heat-shock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis. Circulation. 2001; 103 1503-1508
12 Prohaszka Z, Duba J, Horvath L, Csaszar A, Karadi I, Szebeni A, Singh M, Fekete B, Romics L, Fust G. Comparative study on antibodies to human and bacterial 60 kDa heat shock proteins in a large cohort of patients with coronary heart disease and healthy subjects. Eur J Clin Invest. 2001; 31 285-292
13 Zhu J, Quyyumi A A, Rott D, Csako G, Wu H, Halcox J, Epstein S E. Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis. Circulation. 2001; 103 1071-1075
14 Pockley A G. Heat shock proteins, inflammation, and cardiovascular disease. Circulation. 2002; 105 1012-1017
15 Kervinen H, Huittinen T, Vaarala O, Leinonen M, Saikku P, Manninen V, Manttari M. Antobodies to human heat shock protein 60, hypertension and dyslipidemia. A study of joint effects on coronary risk. Atherosclerosis. 2003; 169 339-344
16 Staub H L, Norman G L, Crowther T, da Cunha V R, Polanczyk A, Bohn J M, Fernandez J G, Chahade W H, von Muhlen C A. Antibodies to the atherosclerotic plaque components beta2-glycoprotein I and heat-shock proteins as risk factors for acute cerebral ischemia. Arq Neuropsiquiatr. 2003; 61(3B) 757-763
17 Vozarova B, Fernández-Real J M, Knowler W C, Gallart L, Hanson R L, Gruber J D, Ricart W, Vendrell J, Richart C, Tataranni P A, Wolford J K. The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians. Hum Genet. 2003; 112 409-413
18 Illig T, Bongardt F, Schöpfer A, Müller-Scholze S, Rathmann W, Koenig W, Thorand B, Vollmert C, Holle R, Kolb H, Herder C . Significant association of the interleukin-6 gene polymorphisms C-174G and A-598G with type 2 diabetes. J Clin Endocrinol Metab. 2004; 89 5053-5058
19 Rathmann W, Haastert B, Icks A, Lowel H, Meisinger C, Holle R, Giani G. High prevalence of undiagnosed diabetes mellitus in Southern Germany: Target populations for efficient screening. The KORA survey 2000. Diabetologia. 2003; 46 182-189
20 Rifai N, Tracy R P, Ridker P M. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem. 1999; 45 2136-2141
21 Hoffmeister A, Rothenbacher D, Bazner U, Frohlich M, Brenner H, Hombach V, Koenig W. Role of novel markers of inflammation in patients with stable coronary heart disease. Am J Cardiol. 2001; 87 262-266
22 Illig T, Bongardt F, Schöpfer A, Holle R, Müller S, Rathmann W, Koenig W, Meisinger C, Wichmann H E, Kolb H, for the KORA Study Group. The endotoxin receptor TLR4 is not associated with diabetes or components of the metabolic syndrome. Diabetes. 2003; 52 2861-2864
23 Schmidt M I, Duncan B B, Sharrett A R, Lindberg G, Savage P J, Offenbacher S, Azambuja M I, Tracy R P, Heiss G, for the ARIC Investigators. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet. 1999; 353 1649-1652
24 Festa A, D'Agostino R, Tracy R P, Haffner S M. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes. The Insulin Resistance Atherosclerosis Study. Diabetes. 2002; 51 131-1137
25 Hanson R L, Imperatore G, Bennett P H, Knowler W C. Components of the ”metabolic syndrome” and incidence of type 2 diabetes. Diabetes. 2002; 51 3120-3127
26 Thorand B, Lowel H, Schneider A, Kolb H, Meisinger C, Frohlich M, Koenig W. C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984 - 1998. Arch Intern Med. 2003; 163 93-99
27 Humphries S E, Luong L A, Ogg M S, Hawe E, Miller G J. The interleukin-6 - 174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J. 2001; 22 2243-2252
28 Brull D J, Leeson C PM, Montgomery H E, Mullen M, de Divitiis M, Humphries S E, Deanfield J E. The effect of the interleukin-6-174G > C promoter gene polymorphism on endothelial function in healthy volunteers. Eur J Clin Invest. 2002; 32 53-157
29 Jenny N S, Tracy R P, Ogg M S, Luong le A, Kuller L H, Arnold A M, Sharrett A R, Humphries S E. In the elderly, interleukin-6 plasma levels and the -174G > C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002; 22 2066-2071
30 Jerrard-Dunne P, Sitzer M, Risley P, Steckel D A, Buehler A, von Kegler S, Markus H S. Carotid Atherosclerosis Progression Study Interleukin-6 promoter modulates the effects of heavy alcohol consumption on early carotid artery atherosclerosis: the Carotid Atherosclerosis Progression Study (CAPS). Stroke. 2003; 34 402-407
31 Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes. Horm Metab Res. 2003; 35 147-152
32 Veres A, Prohászka Z, Kilpinen S, Singh M, Füst G, Hurme M. The promoter polymorphism of the IL-6 gene is associated with levels of antibodies to 60-kDa heat-shock proteins. Immunogenetics. 2002; 53 851-856
33 Xu Q, Kleindienst R, Waitz W, Dietrich H, Wick G. Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest. 1993; 91 2693-2702
34 Xu Q, Schett G, Seitz S, Hu Y, Gupta R S, Wick G. Surface staining and cytotoxic activity of heat shock protein 60 antibody on stressed aortic endothelial cells. Circ Res. 1994; 75 1078-1085
35 Schett G, Xu Q, Amberger A, van der Zee R, Recheis H, Willeit J, Wick G. Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest. 1995; 96 2569-2577
36 Schett G, Metzler B, Kleindienst R, Amberger A, Recheis H, Xu Q, Wick G. Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the anti-hsp65 immune response. Cardiovasc Res. 1999; 42 685-695
37 Xu Q, Schett G, Perschinka H, Mayr M, Egger G, Oberhollenzer F, Willeit J, Kiechl S, Wick G. Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation. 2000; 102 14-20
38 Keren P, George J, Shaish A, Levkovitz H, Janakovic Z, Afek A, Goldberg I, Kopolovic J, Keren G, Harats D. Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice. Establishment of a combined model and association with heat shock protein 65 immunity. Diabetes. 2000; 49 1064-1069

Hubert Kolb, PhD

German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich Heine University

Auf"m Hennekamp 65 · 40225 Düsseldorf · Germany ·

Phone: +49 (211) 3382-643

Fax: +49 (211) 3382-360

Email: kolb@ddfi.uni-duesseldorf.de