Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes
Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes
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DOI：
10.1038/ng1604
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发表时间：
2005-08-01
期刊：
影响因子：
30.8
通讯作者：
Froguel, P
中科院分区：
文献类型：
--
作者：
Meyre, D;Bouatia-Naji, N;Froguel, P
我们在染色体6q16.3-q24.2(参考文献)上发现了一个基因座。1)与儿童肥胖症有关，包括2.4Mb，常见于8次2型糖尿病(T2D)或肥胖症(1-8)的基因组扫描。对6,147名受试者的胰岛素抵抗候选基因ENPP1(也称为PC-1)的分析表明，三个等位基因单倍型(K121Q，IVS20delT-11和A-gt；G+1044TGA；QdelTG)与儿童肥胖(OR=1.69，P=0.0006)、成人中的病态或中度肥胖(OR=1.5，P=0.006或OR=1.37，P=0.02)和T2D(OR=1.56，P=0.00002)有关。IBD基因共享测试表明，这种肥胖相关的ENPP1风险单倍型与观察到的6q染色体与儿童肥胖症有关。单倍型增加了肥胖儿童及其父母患糖耐量异常和T2D的风险，并与儿童血清中可溶性ENPP1蛋白水平的升高有关。包括肥胖相关的A->；G+1044TGA SNP在内的一个长ENPP1 mRNA亚型的表达是胰岛β细胞、脂肪细胞和肝脏所特有的。这些发现表明，ENPP1的几个变体在介导胰岛素抵抗以及肥胖症和T2D的发展中起着主要作用，这表明潜在的分子机制在这两种情况下都是共同的。
We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity(1-8). Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance(9,10), in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A -> G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A -> G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.