Association of the TNF‐α−308 G/A Promoter Polymorphism with Insulin Resistance in Obesity

Abstract

2002;10:401-407. Objective: Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)-␣ is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (Ϫ308 G/A) of the TNF-␣ 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 Ͻ 0.001), higher HOMA scores (10.2 vs. 5.3; p Ͻ 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p ϭ 0.02), and lower high-density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p ϭ 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 ϭ Ϫ0.710; p Ͻ 0.001) occurred in subjects with the A allele only. Discussion: The Ϫ308 G/A TNF-␣ 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.

Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension

“…Finally, a common polymorphism in the promoter region of the TNF-a gene has been associated to increased TNF-a and systolic BP. 35 Contrary to previous studies aimed to test this hypothesis, 6,7,36 we did not find a significant association between CRP and hypertensive status. In our analysis the effect of CRP may be absent due to the inclusion of TNF-a and IL-6 in the final model.…”

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

“…Indeed, gene polymorphisms of TNF have been associated with obesity by many investigators. [24][25][26][27][28][29][30][31] Infiltrative macrophages have been shown to be increased and to be the main source of TNF-a expression in adipose tissue in obese mice. 32,33 MIF could upregulate TNF-a secretion by macrophages.…”

Association studies of genetic polymorphisms in central obesity: a critical review

“…104,105 Some, but not all studies, have indicated a key role for the À308 variant of the TNF gene in the pathogenesis of obesity and obesity-associated insulin resistance. [57][58][59][106][107][108][109][110][111] However, only four of these studies include anthropometric indices of central obesity. 57,58,110,111 Among these studies, two reported associations between the GÀ308A variant of the TNF and measurements of central obesity.…”

“…[57][58][59][106][107][108][109][110][111] However, only four of these studies include anthropometric indices of central obesity. 57,58,110,111 Among these studies, two reported associations between the GÀ308A variant of the TNF and measurements of central obesity. 57,58 In one of the negative studies, men homozygous for the A allele had a trend toward greater central adiposity and higher insulin and glucose levels.…”

“…13 By contrast, only a few of these studies give sufficient attention to phenotypes reflecting central obesity (eg abdominal visceral fat, WHR, waist circumference, sagittal abdominal diameter). Table 1 54,55 peroxisome proliferative activated receptor g, coactivator 1 (PPARGC1), 56 tumor necrosis factor (TNF), 57,58 tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), 59 uncoupling protein 2 (UCP2), 60 and uncoupling protein 3 (UCP3). 61 In addition to the positive association studies summarized in Table 1, the number of 'negative' reports, which are only partly reviewed below, is also increasing very rapidly.…”