Schäffler A, Palitzsch K D, Watzlawek E, Drobnik W, Schwer H, Schölmerich J, Schmitz G
Department of Internal Medicine I; Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany.
Eur J Clin Invest. 1999 Sep;29(9):770-9. doi: 10.1046/j.1365-2362.1999.00529.x.
The recently described A-->G (-3826) point mutation within the distal region of the UCP-1 promoter is possibly involved in the development of obesity, diabetes and related metabolic disorders. It was the aim of this study to examine the allelic frequency and the prevalence of the three UCP-1 genotypes in a broad caucasian cohort and to investigate the significance of this polymorphism for obesity and diabetes.
1020 subjects were randomly chosen from 6450 participants in the Diabetomobile Study. The UCP-1 genotype was determined by genomic PCR and Bcl-I-RFLP analysis in 1020 subjects and tested for association with a variety of metabolic parameters. In addition, the influence of this mutation on adipocyte nuclear factor binding was investigated by electrophoretic mobility shift assays (EMSA).
The genotype frequencies in 1020 subjects were: AA genotype, 57.0%; AG genotype, 35.4%; GG genotype, 7.6%; with allelic frequencies of 0.75 for allele A and 0.25 for allele G. No significant differences between the genotypes and age, gender, BMI, leptin, glucose, fasting insulin, C-peptide, HbA1c, diabetes manifestation, total cholesterol, and HDL cholesterol were found. Analysis of the Trp64Arg polymorphism of the beta3-adrenergic receptor in a subgroup of 343 subjects revealed no additive effect to the UCP-1 polymorphism. An yet unknown adipocyte-specific factor of nuclear extracts from 3T3-L1 adipocytes during differentiation is able to bind specifically to the distal UCP-1 promoter region and this binding ability can not be abolished by the mutation.
We determined the genotype and allelic frequency of the UCP-1 promoter polymorphism in the largest known population-based study. The results from genotyping demonstrate clearly that this polymorphism does not play a major role in the pathogenesis obesity and diabetes. A yet unknown adipocyte derived and differentiation-dependent regulated transcription factor is able to bind to the distal UCP-1 promoter surrounding -3826 bp. This binding is not affected by presence of the mutation.
最近描述的UCP - 1启动子远端区域的A→G（-3826）点突变可能与肥胖、糖尿病及相关代谢紊乱的发生有关。本研究的目的是在一个广泛的白种人队列中检测三种UCP - 1基因型的等位基因频率和患病率，并研究这种多态性对肥胖和糖尿病的意义。
从糖尿病移动研究的6450名参与者中随机选取1020名受试者。通过基因组PCR和Bcl - I - RFLP分析确定1020名受试者的UCP - 1基因型，并检测其与各种代谢参数的关联。此外，通过电泳迁移率变动分析（EMSA）研究该突变对脂肪细胞核因子结合的影响。
1020名受试者的基因型频率为：AA基因型，57.0%；AG基因型，35.4%；GG基因型，7.6%；等位基因A的频率为0.75，等位基因G的频率为0.25。未发现基因型与年龄性别、BMI、瘦素、葡萄糖、空腹胰岛素、C肽、糖化血红蛋白、糖尿病表现、总胆固醇和高密度脂蛋白胆固醇之间存在显著差异。对343名受试者亚组中的β3 - 肾上腺素能受体的Trp64Arg多态性分析显示，对UCP - 1多态性无累加效应。3T3 - L1脂肪细胞分化过程中核提取物中一种未知的脂肪细胞特异性因子能够特异性结合到UCP - 1启动子远端区域，且这种结合能力不会因突变而消除。
在已知最大的基于人群的研究中，我们确定了UCP - 1启动子多态性的基因型和等位基因频率。基因分型结果清楚地表明，这种多态性在肥胖和糖尿病的发病机制中不发挥主要作用。一种未知的源自脂肪细胞且受分化调控的转录因子能够结合到-3826 bp附近的UCP - 1启动子远端区域。这种结合不受突变存在的影响。
