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首页> 外文期刊>Nature >A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes
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A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

机译：常见的格陵兰TBC1D4变异型可赋予肌肉胰岛素抵抗和2型糖尿病

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摘要

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 mat homozygous carriers of this variant havemarkedlyhigherconcentrationsofplasmaglucose(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=-0.18mmol 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 ofskeletal 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 traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.
机译：格陵兰岛人口是一个小规模的，历史悠久且孤立的创始人口，约有57,000名居民，在过去25年中，其2型糖尿病（T2D）患病率急剧上升。因此，我们在多达2575名无已知糖尿病的格陵兰人中进行了T2D相关定量性状的关联映射。使用基于阵列的基因分型和外显子组测序，我们发现了一个无意义的p。基因TBC1D4中的Arg684Ter变体（其中精氨酸被终止密码子替代）的等位基因频率为17％。在这里我们显示了该变体的纯合子携带者具有明显更高的血浆葡萄糖浓度（β= 3.8 mmol l〜（-1），P = 2.5×10〜（-35））和血清胰岛素（β= 165 pmol l〜（-1），P =与其他基因型个体（非携带者和杂合携带者）相比，口服葡萄糖负荷后2小时1.5×10〜（-20））。此外，纯合子携带者的空腹血浆葡萄糖（β= -0.18mmol l〜（-1），P = 1.1×10〜（-6））和空腹血清胰岛素（β= -8.3 pmol l〜（- 1），P = 0.0014），并且他们的T2D风险显着增加（赔率（OR）= 10.3，P = 1.6×10〜（-24））。口服葡萄糖负荷后2小时，杂合型携带者的血浆葡萄糖浓度要比非携带者高（β= 0.43 mmol l〜（-1），P = 5.3×10〜（-5））。骨骼肌活检分析表明，p.Arg684Ter等位基因数量增加，TBC1D4的长同工型的信使RNA和蛋白水平降低，葡萄糖转运蛋白GLUT4的肌蛋白水平降低。这些发现与胰岛素刺激的肌肉中葡萄糖摄取的严重减少有关，从而导致餐后高血糖，糖耐量降低和T2D。在这些特征的大规模全基因组关联研究中，观察到的效应大小比以前的发现大几倍，并进一步证明了在大型同质种群传统设置之外进行遗传关联研究的价值。

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  • 来源
    《Nature》 |2014年第7513期|190-193|共4页
  • 作者

    Ida Moltke; Niels Grarup; Marit E. Jorgensen; 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;

  • 作者单位

    The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark,Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;

    Steno Diabetes Center, 2820 Gentofte, Denmark;

    National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;

    Department of Integrative Biology, University of California, Berkeley, California 94720, USA;

    Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark,Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Stockholm, Sweden;

    Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark;

    BGI-Shenzhen, Shenzhen 518083, China;

    BGI-Shenzhen, Shenzhen 518083, China;

    BGI-Shenzhen, Shenzhen 518083, China;

    BGI-Shenzhen, Shenzhen 518083, China,The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark,BGI-Shenzhen, Shenzhen 518083, China,The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark,Macau University of Science and Technology, Macau 999078, China;

    Holbaek Hospital, 4300 Holbaek, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;

    Department of Integrative Biology, University of California, Berkeley, California 94720, USA,Department of Statistics, University of California, Berkeley, California 94720, USA;

    The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark;

    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark,Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark;

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