A novel promoter polymorphism in the human gene GNAS affects binding of transcription factor upstream stimulatory factor 1, Galphas protein expression and body weight regulation.

Body weight regulation is under complex control involving the central nervous system and peripheral pathways. The beta-adrenoceptor Galphas protein system plays an important role in heart rate regulation and lipid mobilization suggesting a key role for the stimulatory G protein Galphas in body weight regulation. We sequenced the whole GNAS promoter to identify a functional variant which results in altered Galphas expression. We genotyped 110 participants of a randomized placebo-controlled weight loss trial who were under a low calorie diet and were additionally treated with either placebo or 15 mg sibutramine daily for 54 weeks and associated the respective alleles with regard to treatment outcome using an intention-to-treat analysis. A G>A transition at position -1211 the human GNAS promoter (minor allele frequency=0.36) was identified resulting in altered upstream stimulatory factor 1 transcription factor binding, promoter activity, Galphas expression, and lipolysis. Under a low calorie diet -1211GG genotypes lost significantly more weight compared with A-allele carriers (placebo group: 1211GG, 7.5+/-0.4 versus -1211A, 4.5+/-0.3 kg, P=0.020). Sibutramine was effective only in A-allele carriers whereas GG genotypes showed no additional weight loss under sibutramine but showed the strongest increases in resting heart rate (8.5 bpm; 95% confidence interval: 2.7-14.21 bpm; P=0.005) and systolic blood pressure (9.1 mmHg, 95% confidence interval: 3.1-15.1; P=0.004) compared with placebo. Determination of GNAS promoter alleles may identify obese individuals who lose weight easily under lifestyle changes alone but also those who benefit from adjunct sibutramine therapy.