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.

Obes Res. 2003;11:802-808. Objective: To determine whether the N363S variant in the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1: NR3C1) is associated with obesity, type 2 diabetes, or hypertension. Research Methods and Procedures:This was a crosssectional case-control study involving 951 Anglo-Celtic/ Northern European subjects from Sydney. This study consisted of the following: 1) an obesity clinic group, most of whom had "morbid obesity" (mean BMI for group ϭ 43 Ϯ 8 kg/m 2 ; n ϭ 152); 2) a type 2 diabetes clinic group (n ϭ 356); 3) patients with essential hypertension who had a strong family history (n ϭ 141); and 4) normal healthy controls (n ϭ 302). N363S genotype, BMI, and a range of other parameters relevant to each group were measured. Results: Compared with the frequency of 0.04 in nonobese healthy subjects, the S363 allele was significantly higher in obesity clinic patients (0.17; p ϭ 5.6 ϫ 10 -8 ), subjects with diabetes who were also obese (0.09; p ϭ 0.0045), subjects with hypertension who were also overweight (0.08; p ϭ 0.0016), and overweight healthy subjects (0.12; p ϭ 0.0004). Discussion:The NR3C1 N363S variant is associated with obesity and overweight in a range of patient settings but is not associated with hypertension or type 2 diabetes.

OBJECTIVE: To determine whether the C825T polymorphism of the G-protein b3 subunit gene (GNB3) is associated with overweight and obesity. This polymorphism leads to a splice variant (Gb3-s) with higher activity and very strong association with essential hypertension. DESIGN: A cross-sectional case-control study. SUBJECTS: The sets of affected and control BritishaEuropean Caucasian subjects used were: (i) an obesity clinic group most of whom had`morbid obesity' (mean body mass index (BMI) for group 43 AE 8 kgam 2 ) and non-obese controls (BMI 30); (ii) a group of overweightaobese healthy normotensive community volunteers (BMI b 25; mean 29 AE 5) and controls (BMI 25; mean 23 AE 1); (iii) a group of overweightaobese hypertensive patients (BMI b 25; mean 30 AE 4) and lean hypertensive controls (BMI 25; mean 23 AE 2). MEASUREMENTS: BMI, blood pressure, serum lipids, alleles of GNB3 polymorphism. RESULTS: Compared with control, frequency of the T allele in obese subjects was higher by 12% in (i), 17% in (ii) and 28% in (iii), but the differences were not statistically signi®cant. Slight tracking of the T allele with elevation in BMI was, however, observed, in the obesity clinic group (P 0.018). CONCLUSION: The C825T splice variant of GNB3 makes little if any contribution to obesity in the groups we tested.

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