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一种遗传变异与Ⅱ型糖尿病相关

摘要 : 英国《自然》杂志在线版近日公布的一项研究表明,丹麦遗传学家辨别出了一种遗传变异,正是其增加了调查对象格陵兰岛人罹患Ⅱ型糖尿病的风险。这个存在于17%的研究对象当中的基因变异,会导致餐后血糖调节能力的退化。这种常见的变异对于患Ⅱ型糖尿病风险的影响,远超先前发现的与Ⅱ型糖尿病相关的基因突变。

格陵兰岛人历史上是一个小型而孤立的人群,因此具有“奠基者效应”。“奠基者效应”是遗传漂变的一种形式,指的是由很少一群人繁衍出的种群,这个群体后来数量虽然会增加,但因未与其他生物群体交配繁殖,彼此之间基因的差异性甚小。因此,他们患上某种疾病的几率大大高于外界。在格陵兰岛,人们就经历了Ⅱ型糖尿病患病率的急剧增加。和Ⅰ型糖尿病相比,Ⅱ型糖尿病患者体内产生胰岛素的能力并非完全丧失,而是处于一种相对缺乏的状态。

丹麦哥本哈根大学托本·汉森和他的研究团队,从2575个格陵兰岛人当中筛选和Ⅱ型糖尿病相关性状有关的遗传变异。他们发现,一个名叫TBC1D4基因中的突变,会让研究对象在口服相当于一顿饭的葡萄糖两个小时后,血液中的葡萄糖和胰岛素含量更高,从而增加Ⅱ型糖尿病的患病风险。

到目前为止,科学家还无法控制人体的遗传因素,一直依靠对环境因素进行干预,从而降低Ⅱ型糖尿病的患病率。此次研究和过往的Ⅱ型糖尿病相关性状的大规模全基因组关联分析相比,新观察到的遗传变异带来的影响大了好几倍。

同时,在传统上,基因关联分析都在大规模的混合人群中进行,但这项研究表明,在孤立的小种群进行这种调查能提供有价值的结果。

原文摘要:

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

Ida Moltke, Niels Grarup, Marit E. Jørgensen, Peter Bjerregaard, Jonas T. Treebak, Matteo Fumagalli, Thorfinn S. Korneliussen, Marianne A. Andersen, Thomas S. Nielsen, Nikolaj T. Krarup, Anette P. Gjesing, Juleen R. Zierath, Allan Linneberg, Xueli Wu, Guangqing Sun,Xin Jin, Jumana Al-Aama, Jun Wang, Knut Borch-Johnsen, Oluf Pedersen, Rasmus Nielsen, Anders Albrechtsen & Torben Hansen

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l−1, P = 2.5 × 10−35) and serum insulin (β = 165 pmol l−1, P = 1.5 × 10−20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = −0.18 mmol l−1, P = 1.1 × 10−6) and fasting serum insulin (β = −8.3 pmol l−1, P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10−24). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l−1, P = 5.3 × 10−5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2, 3, 4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

对应Nature杂志: 2014年8月14日Nature杂志精选

来源: 科技日报 浏览次数:94

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