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Significant Association of the Interleukin-6 Gene Polymorphisms C-174G and A-598G with Type 2 Diabetes

Institute of Epidemiology (T.I., F.B., A.S., B.T., C.V.) and Institute of Health Economics and Health Care Management (R.H.), GSF National Research Centre for Environment and Health, D-85764 Neuherberg, Germany; German Diabetes Centre (S.M.-S., H.K., C.H.) and Department of Biometrics and Epidemiology (W.R.), German Diabetes Research Institute at the University of Düsseldorf, D-40225 Düsseldorf, Germany; and Department of Internal Medicine II-Cardiology, University of Ulm, Medical Centre (W.K.), D-89081 Ulm, Germany

Address all correspondence and requests for reprints to: Wolfgang Koenig, M.D., Department Internal Medicine II-Cardiology, University of Ulm, Medical Centre, Oberer Eselsberg, Robert-Koch-Strasse 8, D-89081 Ulm, Germany. E-mail: wolfgang.koenig{at}medizin.uni-ulm.de.

Elevated blood concentrations of IL-6 have been shown to predict type 2 diabetes. Because the impact of IL-6 gene polymorphisms on diabetes status, parameters of the metabolic syndrome, and low-grade systemic inflammation has not been analyzed in a population-based study, we investigated the association of the IL-6 single nucleotide polymorphisms C-174G and A-598G on these parameters in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. Both –174G and –598G alleles were significantly associated with type 2 diabetes (-174G: odds ratio = 1.51, 95% confidence interval = 1.11–2.07, P = 0.0096; –598G: odds ratio = 1.56, 95% confidence interval = 1.13–2.15, P = 0.0069) but not with impaired glucose tolerance. In subgroup analyses, the association reached statistical significance in men and in leaner subjects (body mass index 28.7 kg/m², i.e. study median) but not in women or more obese persons. Circulating IL-6 levels were not associated with the IL-6 polymorphisms, but significantly elevated levels of the chemokine monocyte chemoattractant protein-1/CC chemokine ligand 2 in carriers of the protective genotypes indicated an indirect effect of these single nucleotide polymorphisms on the innate immune system. Our findings confirm that immune gene polymorphisms can be considered as independent risk factors in the etiology of type 2 diabetes and suggest that their contribution may be indirect, by influencing the levels of other immune mediators like monocyte chemoattractant protein-1.

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