Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients

OBJECTIVE - Mice lacking the tumor necrosis factor-alpha receptor 2 (TNFR2) gene fed a high-fat diet gain less weight and display reduced leptin and i nsulin levels. In humans, plasma levels of the soluble fraction of TNFR2 (s TNFR2) circulate in proportion to the degree of insulin resistance. The pur pose of this study was to evaluate a polymorphism in the 3' untranslated re gion of the TNFR2 gene on chromosome 1 in relation to BMI, leptin levels, a nd insulin resistance. RESEARCH DESIGN AND METHODS - Using single-strand conformation polymorphism , the polymorphism was analyzed in 107 nondiabetic subjects (60 women, 47 m en) and in 110 consecutive patients with type 2 diabetes (79 women, 31 men) . In a subset of 33 healthy subjects, insulin sensitivity (minimal model an alysis) was also evaluated. RESULTS - Four alleles of the TNFR2 gene were identified (A1, A2, A3, and A 4). BMI and serum leptin levels were significantly increased in young carri ers of the A2 allele. Plasma sTNFR2 levels were similar among the different TNFR2 gene variants. However, in subjects who did not carry the A2 allele, in young subjects, and in women, plasma sTNFR2 levels were proportional to BMI and leptin levels. In the study sample, carriers of the A2 allele (n = 18) showed significantly increased BMI, fat mass, waist-to-hip ratio, seru m total and VLDL triglyceride levels, and leptin levels and had a lower ins ulin sensitivity index than noncarriers of the A2 variant (n = 15). The fre quency of the different alleles among diabetic subjects was similar to that in the control population However, diet-treated diabetic subjects (n = 49) who were carriers of the A2 allele exhibited significantly higher BMI and leptin levels than diet-treated non-carriers of the A2 allele. CONCLUSIONS - The presence of the A2 allele in the TNFR2 gene may predispos e subjects to obesity and higher leptin levels, which may in turn predispos e them to insulin resistance or vice versa. The TNFR2 gene may be involved in weight-control mechanisms.