Abstract:
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.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Frey UH,Hauner H,Jöckel KH,Manthey I,Brockmeyer N,Siffert Wdoi
10.1097/FPC.0b013e3282f49964subject
Has Abstractpub_date
2008-02-01 00:00:00pages
141-51issue
2eissn
1744-6872issn
1744-6880pii
01213011-200802000-00007journal_volume
18pub_type
杂志文章,随机对照试验abstract:OBJECTIVE:To investigate the effect of the Taq1A variant in the Dopamine D2 receptor gene (DRD2) and common functional genetic variants in the cytochrome P450 2D6 gene (CYP2D6) on prolactin levels in risperidone-treated boys with autism spectrum disorders and disruptive behavior disorders. METHODS:Forty-seven physical...
journal_title:Pharmacogenetics and genomics
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journal_title:Pharmacogenetics and genomics
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/01213011-200505000-00004
更新日期:2005-05-01 00:00:00
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doi:10.1097/FPC.0b013e32832fabf3
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pub_type: 杂志文章,meta分析,评审
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更新日期:2014-07-01 00:00:00
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更新日期:2009-12-01 00:00:00
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更新日期:2017-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2012-07-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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更新日期:2005-06-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32801152c2
更新日期:2007-02-01 00:00:00