Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes

Abstract

We identified a childhood obesity locus on chromosome 6q16.3-q24.2 1 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity 1-8 . Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance 9,10 in 6,147 subjects revealed association between a three allele risk haplotype (K121Q/IVS20 delT-11/A>G +1044 TGA, QdelTG) and childhood obesity (OR=1.69, p=0.0006), and in adults with morbid or moderate obesity (OR= 1.50, p= 0.006, OR= 1.37, p= 0.02) and also with T2D (OR=1.56, p=0.00002). The Genotype IBD Sharing Test suggested a contribution of this obesity-associated ENPP1 risk haplotype to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and to their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesityassociated A>G +1044 TGA SNP, was found to be specific for pancreatic islet beta-cells, adipocytes and liver. These findings suggest a primary role for several variants of ENPP1 in mediating insulinresistance, in the development of both obesity and type 2 diabetes, suggesting an underlying molecular mechanism common to both widespread afflictions. Competing interests statementThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2007 October 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInitially, the phenotypic characteristics of 62 "6q-evidence" families (defined by an individual pedigree Zscore > 1.0 in the 2-LOD drop interval flanked by markers D6S434 and D6S1704) were compared with the remaining 35 families from our previously published genome scan for childhood obesity 1 . The "6q-evidence" obese children have a trend towards higher area under the glycemia curve after glucose administration and a significantly lower insulinogenic index (Supplementary Table 1). Compared to none of the other families, 3.1% of the "6q-evidence" obese children are glucose intolerant or diabetic and 13.8% of 6q linked obese children parents have type 2 diabetes mellitus (T2D) compared to 3.2% of parents in other families (p=0.018). Thus, the obesity susceptibility gene(s) on chromosome 6q may be also involved in glucose homeostasis.The "6q-evidence" 2-LOD drop interval 1 covers 41.4 Mb and includes 166 referenced genes. This was narrowed to a 2.4 Mb interval between markers D6S1656 and D6S270 using overlapping published linkage results on chromosome 6q16.1-q27 with either obesity 2 , insulin secretion 3,4 or T2D 5-8 . Within this interval, the best candidate was ectonucleotide pyrophosphatase phosphodiesterase ENPP1 (also known as the Plasma Cell glycoprotein-1 PC-1). ENPP1 is believed to directly inhibit insulin-induced conformational changes of the insulin receptor, thereby affecting its activation and downstream signaling 9,11 .The microsatellite marker D6S1656 in...

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“…Therefore, klotho belongs to the group of key factors regulating mineral and vitamin D metabolism. (c) ENPP1, known to be the gene for insulin resistance/type 2 diabetes, hyperglycemia, and obesity (Meyre et al 2005), was recently shown by us and others to be associated with osteoporosisrelated traits (Cheung et al 2010). (d) Activation of the nuclear protein deacetylase Sirt1 (an antioxidant protein involved in aging) has recently been shown to decrease adipocyte development from preadipocytes, therefore promoting differentiation of mesenchymal stem cells into osteoblasts via inhibition of PPARγ (Backesjo et al 2009).…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…One ENPP1 haplotype is associated with childhood and morbid obesity, T2DM, as well as circulating levels of ENPP1. [144][145][146] Expression of a long ENPP1 mRNA isoform, which includes one of the SNPs defining the risk haplotype, is specific for pancreatic islet beta cells, adipocytes and liver. 144 In addition, one ENPP1 SNP may impair insulin binding to the insulin receptor.…”

“…[144][145][146] Expression of a long ENPP1 mRNA isoform, which includes one of the SNPs defining the risk haplotype, is specific for pancreatic islet beta cells, adipocytes and liver. 144 In addition, one ENPP1 SNP may impair insulin binding to the insulin receptor. 144 Two recent reports including several thousand subjects of European ancestry have not confirmed association between the ENPP1 haplotype and obesity or T2DM.…”

“…144 In addition, one ENPP1 SNP may impair insulin binding to the insulin receptor. 144 Two recent reports including several thousand subjects of European ancestry have not confirmed association between the ENPP1 haplotype and obesity or T2DM. 147,148 The reasons for the failure to confirm association may be the same as that for HSL, see above.…”

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

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