Common variants in HNF-1 α and risk of type 2 diabetes
Common variants in HNF-1 α and risk of type 2 diabetes
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DOI：
10.1007/s00125-006-0450-x
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发表时间：
2006-12-01
期刊：
影响因子：
8.2
通讯作者：
Groop, L.
中科院分区：
文献类型：
--
作者：
Holmkvist, J.;Cervin, C.;Groop, L.
肝细胞核因子1-α基因突变（HNF-1 α，现在称为转录因子1基因[TCF 1]）引起糖尿病的最常见单基因形式MODY 3，但尚不清楚HNF-1 α中的常见变体是否与转录活性降低或与2型糖尿病相关的表型相关，或是否预测未来的2型糖尿病。我们研究了四种常见的多态性的影响，（rs 1920792、I27 L、A98 V和S487 N）对体外转录活性的影响，HNF-1 α基因中I27 L和A98 V多态性的某些组合显示靶启动子葡萄糖转运蛋白2的转录活性降低，（现在称为溶质载体家族2 [易化葡萄糖转运蛋白]，成员2）和白蛋白。在体内，这些多态性与口服葡萄糖引起的胰岛素分泌的适度但显著的损害有关。在携带A98 V多态性V等位基因的个体中，胰岛素分泌随着时间的推移而恶化（n= 2，293; p=0.003）。在一个新的病例对照中，（分别为1，511和2，225）数据集，I27 L多态性与2型糖尿病风险增加相关，比值比（OR）=1.5（p=0.002; P = 0.001）。多元logistic回归），尤其是老年人（年龄> 60岁）和超重（BMI > 25 kg/m2）患者（OR=2.3，p=0.002）。该研究提供了体外和体内证据，表明MODY 3基因的常见变异，HNF-1 α，影响体内转录活性和胰岛素分泌。这些变异与老年超重个体中迟发性2型糖尿病风险的适度增加有关。
Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes.We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo.Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 (p=0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR=2.3, p=0.002).This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.