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Genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects.

ABSTRACT: Hypertriglyceridemia is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. Membrane glycoprotein PC-1 (also termed ENPP1) is a direct insulin receptor inhibitor, and certain polymorphisms of the ENPP1/PC-1 gene have been associated with insulin resistance, type 2 diabetes, obesity, and diabetic complications.We examined the effect of 3 ENPP1/PC-1 variants (K121Q, rs1044498, and IVS20delT-11, rs1799774, and A-->G+1044TGA, rs7754561) on plasma triglyceride levels in 1112 subjects of non-Hispanic American white European ancestry.Two of the ENPP1/PC-1 variants--A-->G+1044TGA (odds ratio [OR] 1.48, 95% confidence interval [CI], 1.54-1.82, P = 0.002) and IVS20delT-11 (OR 1.41, 95% CI, 1.08-1.84, P = 0.012)--were significantly associated with hypertriglyceridemia. Haplotype analyses also revealed an association with hypertriglyceridemia. In the variant analyses and in the haplotype analysis, the associations with hypertriglyceridemia were observed in male but not female subjects. Interestingly, the more widely studied K121Q ENPP1/PC-1 variant was not associated with hypertriglyceridemia in any group or subgroup analysis.In the present study, we find that genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects, and may contribute to the development of the insulin resistance/metabolic syndrome in this population.

SUBMITTER: Tanyolac S

PROVIDER: S-EPMC3139525 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects.

Tanyolaç Sinan S Bremer Andrew A AA Hodoglugil Uğur U Movsesyan Irina I Pullinger Clive R CR Heiner Steven W SW Malloy Mary J MJ Kane John P JP Goldfine Ira D ID

Metabolic syndrome and related disorders 20091201 6

<h4>Background</h4>Hypertriglyceridemia is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. Membrane glycoprotein PC-1 (also termed ENPP1) is a direct insulin receptor inhibitor, and certain polymorphisms of the ENPP1/PC-1 gene have been associated with insulin resistance, type 2 diabetes, obesity, and diabetic complications.<h4>Methods</h4>We examined the effect of 3 ENPP1/PC-1 variants (K121Q, rs1044498, and IVS20delT-11, rs1799774, and A-->G+1044TGA, rs7754561) ...[more]

PMID: 19656007

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Project description:Mineralization of bones and teeth is tightly regulated by levels of extracellular inorganic phosphate (Pi) and pyrophosphate (PPi). Three regulators that control pericellular concentrations of Pi and PPi include tissue-nonspecific alkaline phosphatase (TNAP), progressive ankylosis protein (ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Inactivation of these factors results in mineralization disorders affecting teeth and their supporting structures. This study for the first time analyzed the effect of decreased PPi on dental development in individuals with generalized arterial calcification of infancy (GACI) due to loss-of-function mutations in the ENPP1 gene. Four of the 5 subjects reported a history of infraocclusion, overretained primary teeth, ankylosis, and/or slow orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. All subjects had radiographic evidence of unusually protruding cervical root morphology in primary and/or secondary dentitions. High-resolution micro-computed tomography (micro-CT) analyses of extracted primary teeth from 3 GACI subjects revealed 4-fold increased cervical cementum thickness ( P = 0.00007) and a 23% increase in cementum density ( P = 0.009) compared to age-matched healthy control teeth. There were no differences in enamel and dentin densities between GACI and control teeth. Histology revealed dramatically expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. Micro-CT analysis of Enpp1 mutant mouse molars revealed 4-fold increased acellular cementum thickness ( P = 0.002) and 5-fold increased cementum volume ( P = 0.002), with no changes in enamel or dentin. Immunohistochemistry identified elevated ENPP1 expression in cementoblasts of human and mouse control teeth. Collectively, these findings reveal a novel dental phenotype in GACI and identify ENPP1 genetic mutations associated with hypercementosis. The sensitivity of cementum to reduced PPi levels in both human and mouse teeth establishes this as a well-conserved and fundamental biological process directing cementogenesis across species (ClinicalTrials.gov NCT00369421).

Dataset Information

Genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects.

Publications

Genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects.

Similar Datasets

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