A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes
A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes
复制标题
格陵兰人常见的 TBC1D4 变异会导致肌肉胰岛素抵抗和 2 型糖尿病
DOI：
10.1038/nature13425
复制
发表时间：
2014-08-14
期刊：
影响因子：
64.8
通讯作者：
Hansen, Torben
中科院分区：
文献类型：
--
作者：
Moltke, Ida;Grarup, Niels;Hansen, Torben
格陵兰人口是一个历史上孤立的创始人口，约有57,000居民，在过去的25年里，2型糖尿病（T2D）的患病率急剧上升(1)。受此启发，我们对2,575名没有已知糖尿病的格陵兰人进行了t2d相关数量性状的关联映射。利用阵列基因分型和外显子组测序，我们在TBC1D4基因中发现了一个无义p.a g684ter变异（其中精氨酸被终止密码子取代），等位基因频率为17%。本研究表明，与其他基因型（非携带者和杂合携带者）相比，该变异的纯合子携带者在口服葡萄糖负荷2小时后血浆葡萄糖浓度(β =3.8 mmol l（-1), P = 2.5 X 10(-35)）和血清胰岛素浓度(β = 165 pmol l（-1), P = 1.5 X 10(-20)）明显高于其他基因型（非携带者和杂合子携带者）。此外，纯合子携带者空腹血糖(β = -0.18 mmol l（-1), P = 1.1 X 10(-6)）和空腹血清胰岛素（β = -8.3 mmol l(-1), P = 0.0014）浓度略低，T2D风险显著增加(比值比（OR) = 10.3, P = 1.6 X 10(-24)）。杂合子携带者在口服葡萄糖负荷2小时后的血浆葡萄糖浓度高于非携带者(β = 0.43 mmol l（-1), P = 5.3 X 10(-5)）。骨骼肌活检分析显示，TBC1D4长异构体的信使RNA和蛋白质水平较低，葡萄糖转运蛋白GLUT4的肌肉蛋白水平较低，p.a g684ter等位基因数量增加。这些发现伴有胰岛素刺激的肌肉葡萄糖摄取严重减少，导致餐后高血糖、糖耐量受损和T2D。观察到的效应量比以往在这些性状的大规模全基因组关联研究中发现的效应量大几倍（2-4），并进一步证明了在大型同质群体的传统环境之外进行遗传关联研究的价值。
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(1). 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(beta=3.8 mmol l(-1), P = 2.5 X 10(-35)) and serum insulin (beta = 165 pmol l(-1), P = 1.5 X 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 (beta = -0.18 mmol l(-1), P = 1.1 X 10(-6)) and fasting serum insulin (beta = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 X 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (beta = 0.43 mmol l(-1), P = 5.3 X 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 traits(2-4) and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.