Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V et al.. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 37: 863-867

CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Nature Genetics (Impact Factor: 29.65). 08/2005; 37(8):863-7. DOI: 10.1038/ng1604
Source: PubMed

ABSTRACT 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. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, 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.

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    • "use disease under certain circumstances . Although the community put a great deal of effort into genome - wide familial linkage studies during 10 years , only a few T2D putative linked regions were identified through this strategy : CAPN10 ( Hanis et al . , 1996 ) , ADIPOQ ( Vionnet et al . , 2000 ) , HNF4A ( Si - lander et al . , 2004 ) , ENPP1 ( Meyre et al . , 2005 ) , and TCF7L2 ( Grant et al . , 2006 ) . Yet , only the associations of HNF4A and TCF7L2 loci with T2D risk were subsequently replicated by GWAS analyses , casting doubt about the contribution of the others ( Figure 2 ) ( Kooner et al . , 2011 ; Sladek et al . , 2007 ) . Impor - tantly , the hypothesis of major genes involved in common"
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    ABSTRACT: Type 2 diabetes (T2D) had long been referred to as the "geneticist's nightmare." Genome-wide association studies have fully confirmed the polygenic nature of T2D, demonstrating the role of many genes in T2D risk. The increasingly busier picture of T2D genetics is quite difficult to understand for the diabetes research community, which can create misunderstandings with geneticists, and can eventually limit both basic research and translational outcomes of these genetic discoveries. The present review wishes to lift the fog around genetics of T2D with the hope that it will foster integrated diabetes modeling approaches from genetic defects to personalized medicine. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 01/2015; 21(3). DOI:10.1016/j.cmet.2014.12.020 · 16.75 Impact Factor
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    • "NPP1 expression has now been demonstrated in a wide range of tissues and cell types including the heart, kidney, vascular smooth muscle cells and chondrocytes [9] [10] [11] [12]. In addition to its role in regulating mineralisation, NPP1 is also thought to be involved in glucose homeostasis and insulin signalling [13] [14] [15]. Mutations in the gene encoding NPP1 (Enpp1) have been associated with a rare autosomal recessive disease generalised arterial calcification of infancy (GACI) [16]. "
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    ABSTRACT: Ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs) hydrolyse nucleotide triphosphates to the corresponding nucleotide monophosphates and the mineralisation inhibitor, pyrophosphate (PPi). This study examined the role of NPP1 in osteocytes, osteoclasts and cortical bone, using a mouse model lacking NPP1 (Enpp1(-/-)). We used microcomputed tomography (μCT) to investigate how NPP1 deletion affects cortical bone structure; excised humerus bones from 8, 15 and 22-week old mice were scanned at 0.9μm. Although no changes were evident in the cortical bone of 8-week old Enpp1(-/-) mice, significant differences were observed in older animals. Cortical bone volume was decreased 28% in 22-week Enpp1(-/-) mice, whilst cortical porosity was reduced 30% and 60% at 15 and 22-weeks, respectively. This was accompanied by up to a 15% decrease in closed pore diameter and a 55% reduction in the number of pores. Cortical thickness was reduced up to 35% in 15 and 22-week Enpp1(-/-) animals and the endosteal diameter was increased up to 23%. Thus, the cortical bone from Enpp1(-/-) mice was thinner and less porous, with a larger marrow space. Scanning electron microscopy (SEM) revealed a decrease in the size and number of blood vessel channels in the cortical bone as well as a 40% reduction in the mean plan area of osteocyte lacunae. We noted that the number of viable osteocytes isolated from the long bones of Enpp1(-/-) mice was decreased ≤50%. In contrast, osteoclast formation and resorptive activity was unaffected by NPP1 deletion. μCT and histological analysis of Enpp1(-/-) mice also revealed calcification of the joints and vertebrae as well as soft tissues including the whisker follicles, ear pinna and trachea. This calcification worsened as the animals aged. Together, these data highlight the key role of NPP1 in regulating calcification of both soft and skeletal tissues.
    Bone 09/2014; 69. DOI:10.1016/j.bone.2014.09.016 · 4.46 Impact Factor
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    • "In addition to rs1044498, other ENPP1/PC-1 variants have been reported to modulate insulin resistance-related metabolic disturbances. In a large study [29], a threepolymorphism " risk haplotype " of the ENPP1 gene has been described to be associated with obesity and T2D in both children and adults. This haplotype included the previously reported Q121 allele variant and two functionally uncharacterized noncoding polymorphisms: rs1799774-/T and rs7754561A/G, the latter being located in the 3 í® í° UTR, which might be involved in the modulation of gene expression . "
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    ABSTRACT: Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis.
    Comparative and Functional Genomics 05/2013; 2013:376454. DOI:10.1155/2013/376454 · 1.75 Impact Factor
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