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首页> 外文期刊>Pharmacogenetics and genomics >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.
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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.

机译：人基因GNAS中的新型启动子多态性影响转录因子上游刺激因子1的结合，Galphas蛋白表达和体重调节。

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OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
机译：目的：体重调节处于复杂的控制之下，涉及中枢神经系统和外周途径。 β-肾上腺素能受体Galphas蛋白系统在心率调节和脂质动员中起重要作用，暗示刺激性G蛋白Galphas在体重调节中起关键作用。方法：我们对整个GNAS启动子进行了测序，以鉴定导致Galphas表达改变的功能性变体。我们对随机安慰剂对照减肥试验的110名参与者进行了基因分型，这些参与者均处于低热量饮食下，并每天接受安慰剂或15 mg西布曲明治疗54周，并根据治疗意图将各个等位基因与治疗结果相关联处理分析。结果：鉴定到人GNAS启动子在-1211位置发生G> A转换（次要等位基因频率= 0.36），导致上游刺激因子1转录因子结合，启动子活性，Galphas表达和脂解作用发生改变。与A等位基因携带者相比，低热量饮食下-1211GG基因型的体重明显减轻（安慰剂组：1211GG，7.5 +/- 0.4，而-1211A，4.5 +/- 0.3 kg，P = 0.020）。西布曲明仅在A等位基因携带者中有效，而GG基因型在西布曲明下并未显示出额外的体重减轻，但静息心率（8.5 bpm; 95％置信区间：2.7-14.21 bpm; P = 0.005）的增加最大。 （9.1 mmHg，95％置信区间：3.1-15.1; P = 0.004）与安慰剂相比。结论：确定GNAS启动子等位基因可以鉴定仅在生活方式改变下容易减肥的肥胖者，以及从西布曲明辅助治疗中受益的肥胖者。

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