Genetic Variants of theENPP1/PC-1Gene Are Associated With Hypertriglyceridemia in Male Subjects

Tanyolaç, Sinan; Bremer, Andrew A.; Hodoğlugil, Uğur; Movsesyan, B.S. Irina; Pullinger, Clive R.; Heiner, Ed.D. Steven W.; Malloy, Mary J.; Kane, John P.; Goldfine, Ira D.

doi:10.1089/met.2009.0027

Cited by 17 publications

(7 citation statements)

References 29 publications

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“…Among MetS individuals carrying the KQ/QQ genotype, higher values of TG and insulin resistance reflected by HOMA-IR indicated insulin resistance in MetS patients. Recently, a study has demonstrated that the ENPP1 gene polymorphism is associated with hypertriglyceridemia and may contribute to insulin resistance or MetS [37]. Our results are similar to those of a vast majority of studies carried out in different populations.…”

Section: Discussionsupporting

confidence: 89%

ENPP1 K121Q Functional Variant Enhances Susceptibility to Insulin Resistance and Dyslipidemia with Metabolic Syndrome in Asian Indians

Bhatti

Kaur

Vijayergiya

et al. 2018

Dubai Diabetes Endocrinol J

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Background: Ectonucleotide pyrophosphatase/phosphodiesterase1 (ENPP1/PC-1) is a key modulator of the insulin signaling pathway, and its common variant, K121Q, increases the susceptibility to diabetes and cardiovascular diseases. Objectives: The main objective of the present study was to investigate the association of ENPP1 K121Q polymorphism with the pathophysiology of metabolic syndrome (MetS) in a north Indian population. Methods: A total of 567 participants (303 MetS subjects and 264 healthy controls) were examined for ENPP1 genotypes and various clinical parameters, including body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressures (SBP/DBP), fasting blood glucose (FBG), cholesterol, triglycerides (TG), high-density lipoprotein, and insulin. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analysis of the data was done using SPSS. Results: Significant increases in BMI, WC, SBP, DBP, FBG, TG, low-density lipoprotein, insulin, and Homeostasis Model Assessment of insulin resistance (HOMA-IR) and of beta-cell function (HOMA-BF) were observed in MetS patients compared to healthy controls. Logistic regression analysis of data demonstrated a nonsignificant association of QQ and KQ+QQ genotypes with increased risk of MetS (OR [95% CI], 1.583 [0.455–5.507], p = 0.470 for QQ genotypes and 1.097 [0.784–1.540], p = 0.587 for KQ+QQ genotypes). Moreover, MetS subjects carrying Q alleles had significantly higher levels of TG, insulin, body fat percentage, and insulin resistance as evident by higher values of HOMA-IR. Conclusions: We conclude that ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia in MetS subjects of an Asian Indian population.

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Section: Discussionsupporting

confidence: 89%

ENPP1 K121Q Functional Variant Enhances Susceptibility to Insulin Resistance and Dyslipidemia with Metabolic Syndrome in Asian Indians

Bhatti

Kaur

Vijayergiya

et al. 2018

Dubai Diabetes Endocrinol J

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“…Multiple linkage studies have associated the chromosome locus mapping ENPP1, to insulin resistance [90,93,94], hyperglyceridaemia [95], childhood and adult obesity and increased risk of type 2 diabetes [8]. Furthermore, specific polymorphisms have been identified, of which Lys121Gln (K121Q) [96] is the most widely investigated.…”

Section: Insulin Signalling and Glucose Homeostasismentioning

confidence: 99%

New insights into NPP1 function: Lessons from clinical and animal studies

Mackenzie

Huesa

Rutsch

et al. 2012

Bone

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The recent elucidation of rare human genetic disorders resulting from mutations in ectonucleotide pyrophosphotase/phosphodiesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), has highlighted the vital importance of this molecule in human health and disease. Generalised arterial calcification in infants (GACI), a frequently lethal disease, has been reported in recessive inactivating mutations in ENPP1. Recent findings have also linked hypophosphataemia to a lack of NPP1 function. A number of human genetic studies have indicated that NPP1 is a vital regulator that influences a wide range of tissues through various signalling pathways and when disrupted can lead to significant pathology. The function of Enpp1 has been widely studied in rodent models, where both the mutant tiptoe walking (ttw/ttw) mouse and genetically engineered Enpp1(-/-) mice show significant alterations in skeletal and soft tissue mineralisation, calcium/phosphate balance and glucose homeostasis. These models therefore provide important tools with which to study the potential mechanisms underpinning the human diseases associated with altered NPP1. This review will focus on the recent advances in our current knowledge of the actions of NPP1 in relation to bone disease, cardiovascular pathologies and diabetes. A fuller understanding of the mechanisms through which NPP1 exerts its pathological effects may stimulate the development of novel therapeutic strategies for patients at risk from the devastating clinical outcomes associated with disrupted NPP1 function.

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“…[6][7][8][9] ENPP1 lies on chromosome 6q22-q23 (OMIM#173335) in a region where several independent studies found a linkage peak to OB phenotypes. [10][11][12][13] ENPP1 is an attractive candidate gene for studying OB, as it was proposed as a key player in the etiology of insulin resistance 14,15 and in a recently suggested mechanism underlying defective adipocyte maturation. 16 The ENPP1 product has also been identified as one of the central regulators of extracellular pyrophosphate (ePPi)/phosphate (Pi) equilibrium levels.…”

Section: Introductionmentioning

confidence: 99%

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

et al. 2010

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Background: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. Aim: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. Subjects and methods: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. Results: Associations were observed between ENPP1 polymorphisms and BMI (P ¼ 0.0037) and leptin (P ¼ 0.0068). ALPL markers were associated with WHR (P ¼ 0.0026) and EGFR (P ¼ 0.0001). The ANKH gene was associated with all four studied obesity-related traits (Po0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. Conclusion: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

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Genetic Variants of theENPP1/PC-1Gene Are Associated With Hypertriglyceridemia in Male Subjects

Cited by 17 publications

References 29 publications

<b><i>ENPP1</i></b> K121Q Functional Variant Enhances Susceptibility to Insulin Resistance and Dyslipidemia with Metabolic Syndrome in Asian Indians

<b><i>ENPP1</i></b> K121Q Functional Variant Enhances Susceptibility to Insulin Resistance and Dyslipidemia with Metabolic Syndrome in Asian Indians

New insights into NPP1 function: Lessons from clinical and animal studies

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

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