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Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-α and interleukin-1β polymorphisms Volume 16, numéro 4, December 2005

Auteurs
Department of Anesthesiology and Intensive Therapy, Semmelweis University, Budapest, Research Group of Pediatrics and Nephrology, Hungarian Academy of Science, Budapest, Third Department of Medicine, Semmelweis University and Research Group of Metabolism and Atherosclerosis, Hungarian Academy of Sciences, Budapest, First Department of Paediatrics, Semmelweis University, Budapest, Kiss Áron u. 22/A, H-1125 Budapest, Hungary

Multiple immune mediators have been mentioned as playing a role in the pathomechanism of type1 DM. Interleukin (IL)-1β, and tumor necrosis factor (TNF)-α play a central role in the autoimmune destruction of pancreatic β-cells, whereas IL-6 inhibits TNF-α secretion, and may have some protecting effects. In our study, we aimed to investigate the association between these three cytokines’ single nucleotide polymorphisms (IL-6 gene G(-174)C, TNF-α gene G(-308)A and IL-1β gene C(3954)T polymorphisms) and age-at-onset of type 1 diabetes mellitus (T1DM) in 165 diabetic children (median age: 17 years). Polymorphisms were determined using the PCR-RFLP method. We found that the age-at-onset of T1DM was significantly different in patients with a different IL-6 genotype (median age-at-onset of T1DM was: 8, 6 and 4.5 years in children with the (-174)GG, GC and CC genotypes, respectively; p < 0.01). Adjusted for TNF-α and IL-1β polymorphisms, patients with a IL-6 (-174)CC genotype have a 3.0-fold (95% CI: 1.2-7.1) increased risk of developing diabetes before the age of 6 years than (-174)G allele carrier patients. However, we found this association to be present only in patients who carried the TNF-α (-308)A or IL-1β (3954)T allele, i.e. in patients with high TNF-α and high IL-1β producer genotypes. We suppose that in the case of high TNF-α and IL-1β producer genotypes, elevated proinflammatory cytokine levels result in a higher production of IL-6 in (-174)G allele carrier patients. This elevated IL-6 level may have a protective effect against the development of T1DM and may delay the destruction of pancreatic β-cells.