Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity.
OBJECTIVE
Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)-alpha 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-alpha gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population.


METHODS
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.


CONCLUSIONS
The -308 G/A TNF-alpha 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.
Dalziel
Bronwen
B
Human Nutrition Unit, Department of Biochemistry, University of Sydney, Australia. b.dalziel@biochem.usyd.edu.au
Gosby
Alison K
AK
Richman
Rosemary M
RM
Bryson
Janet M
JM
Caterson
Ian D
ID
D000328:Adult; D000483:Alleles; D001794:Blood Pressure; D001823:Body Composition; D001824:Body Constitution; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D008076:Cholesterol, HDL; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha