Objective: Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)‐α is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (−308 G/A) of the TNF‐α gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population.

Research Methods and Procedures: Obese, non‐diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction‐restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance.

Results: The frequencies of the G allele and the A allele were 0.759 and 0.241, respectively. Subjects homozygous for the A allele had higher fasting insulin levels (226 vs. 131 pM; p < 0.001), higher HOMA scores (10.2 vs. 5.3; p < 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p = 0.02), and lower high‐density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p = 0.04) than did subjects homozygous for the G allele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r = −0.710; p < 0.001) occurred in subjects with the A allele only.

Discussion: The −308 G/A TNF‐α gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the A allele.