Interleukin-1 System Gene Polymorphisms Are Associated with Fat Mass in Young Men

in different compartments, measured with dual-energy x-ray absorptiometry. Results: Carriers of the T variant (CT and TT) of the 3953 C to T (FT 0.25) IL-1 gene polymorphism had significantly lower total fat mass (P 0.013) and also significantly reduced arm, leg, and trunk fat, compared with CC individuals. IL-1RN*2 carriers with two repeats of the IL-1RN variable number tandem repeat polymorphism had increased total fat (P 0.036), serum leptin, and fat of trunk and arm as well as serum levels of IL-1RN and IL-1RN production ex vivo. The IL-1-31 polymorphism did not correlate with the fat measurements. Conclusions: The IL-1 system, recently shown to affect fat mass in experimental animals, contains gene polymorphisms that are associated with fat mass in young men. (J Clin Endocrinol Metab 91: 2749–2754, 2006) T HERE IS GROWING evidence of interactions between the regulation of body fat and the immune system. The cytokine IL-6 suppresses body fat mass and enhances energy expenditure in both mice and men (1–3). Another cytokine, IL-1, also exerts proinflammatory effects, and there is some overlap between the effects of IL-1 and IL-6 on immune functions. We and others have recently found indications that the IL-1 system, like IL-6, influences body fat mass. Mice with depleted IL-1 signaling due to knockout of the gene coding for the biologically active IL-1 receptor I (IL-1RI) develop obesity (4). Conversely, mice with enhanced IL-1 activity due to IL-1 receptor antagonist (IL-1RN) gene knockout are lean and resistant to diet-induced obesity (5). The IL-1 system has several components, including two agonists, IL-1 and the less potent IL-1. The biological effects are exerted via the IL-1RI. The binding of IL-1 to IL-1RI can be inhibited by the endogenous receptor antagonist IL1RN. The effect of IL-1 can also be inhibited by binding a second type of IL-1 receptor, IL-1RII. This receptor acts as a decoy and prevents IL-1 from binding IL-1RI. A delicate balance between IL-1 and IL-1RN is of importance for regulation of immune function (6, 7). There are some common polymorphisms that appear to be associated with differences in the activity of the IL-1 system. The C to T single nucleotide polymorphism (SNP) at nucleotide 3953 from the transcription start of the IL-1 gene seems to be functional because it has been associated with increased production of IL-1 in vitro, worsened rheumatoid arthritis, enhanced inflammatory serum parameters, and decreased risk of certain infections (8–11). The T to C SNP at nucleotide 31 from the transcription start of the IL-1 gene has also been associated with changes in biological parameters in vivo (12). The IL-1RN gene contains a polymorphic region in the second intron, which has an 86-bp variable number tandem repeat (VNTR). The presence of two repeats, IL-1RN*2, in this polymorphism has been reported to be associated with serum IL-1RN levels, production of IL-1 in vitro, and occurrence of inflammatory diseases in vivo (7, 12–14). In the present study, we aimed to investigate the association between genetic differences in the IL-1 system and the regulation of body fat. Therefore, common and functional polymorphisms of the IL-1 system were examined in association with several measures of fat mass in a homogenous