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ARTICLE

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

Csaba Hermann^1,5, Dóra Krikovszky², George Füst³, Margit Kovács³, Anna Körner⁴, András Szabó⁴, Ádám Vannay², László Madácsy²

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

* Corresponding Author: C. Hermann,

European Cytokine Network 2005, 16(4), 277-281.

Abstract

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 b-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 b-cells.

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