SGK1基因的变异与不同欧洲人群的胰岛素分泌有关：来自TUEF、EUGENE2和METSIM研究的结果。
Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies.
作者信息
Friedrich Björn, Weyrich Peter, Stancáková Alena, Wang Jianjung, Kuusisto Johanna, Laakso Markku, Sesti Giorgio, Succurro Elena, Smith Ulf, Hansen Torben, Pedersen Oluf, Machicao Fausto, Schäfer Silke, Lang Florian, Risler Teut, Ullrich Susanne, Stefan Norbert, Fritsche Andreas, Häring Hans-Ulrich
机构信息
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
出版信息
PLoS One. 2008;3(11):e3506. doi: 10.1371/journal.pone.0003506. Epub 2008 Nov 5.
HYPOTHESIS
Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans.
METHODS
Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals.
RESULTS
Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUC(C-Peptide)/AUC(Glc) ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMIxrs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI< or =25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC(Ins)/AUC(Glc) (TT: 226+/-7, XG: 246+/-9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71-1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers.
CONCLUSIONS
The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.
假设
血清和糖皮质激素诱导激酶1（SGK1）参与胰岛素分泌的调节，可能是人类2型糖尿病发生的候选基因。
方法
对三个独立的欧洲人群分析SGK1基因（SGK）变异与胰岛素分泌特征的关联。德国TUEF项目提供筛查人群（N = 725），研究了四个标签单核苷酸多态性（rs1763527、rs1743966、rs1057293、rs9402571）。EUGENE2（N = 827）作为检测到的关联的复制队列。最后，在METSIM研究中验证检测到的关联，该研究提供了3798名非糖尿病个体和659名糖尿病（2型）个体。
结果
与筛查人群中纯合野生型TT携带者相比，rs9402571中次要G等位基因携带者在2小时口服葡萄糖耐量试验中的C肽水平显著更高（+10.8%，p = 0.04；显性模型），AUC（C肽）/AUC（葡萄糖）比值更高（+7.5%，p = 0.04）。由于BMI×rs9402571的交互分析对于终点胰岛素分泌具有显著性（p = 0.04），我们以BMI = 25为切点对TUEF队列按BMI进行分层。对胰岛素分泌的影响仅在瘦的TUEF参与者（BMI≤25）中仍然显著。这一发现 在瘦的EUGENE2 rs9402571次要等位基因携带者中得到重复，他们的AUC（胰岛素）/AUC（葡萄糖）显著更高（TT：226±7，XG：246±9；p = 0.019）。相应地，METSIM试验显示rs9402571次要等位基因携带者中2型糖尿病的患病率较低（OR：0.85；95%CI：0.71 - 1.01；p = 0.065，显性模型）。
结论
rs9402571 SGK基因型与瘦的非糖尿病TUEF/EUGENE2参与者胰岛素分泌增加以及METSIM中较低的糖尿病患病率相关。我们在三个独立欧洲人群中的研究支持SGK变异性影响糖尿病风险这一结论。
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