Ectonucleotide Pyrophosphatase/phosphodiesterase 1 Gene Research Articles

Investigating the Impact of ENPP1 Gene's K121Q (RS1044498) Polymorphism in Type 2 Diabetes via an Updated Meta-Analysis

Type 2 Diabetes Mellitus (T2DM) occurs due to a complex relationship of genetic, environmental, and physiological factors, encompassing insufficient pancreatic insulin synthesis, peripheral insulin resistance, and diverse molecular pathways. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) plays a role in insulin regulation, with the K121Q (rs1044498) variant on the ENPP1 gene being a subject of extensive study due to its potential association with T2DM. To comprehensively evaluate this relationship, a meta-analysis was conducted, pooling data from 48 studies retrieved from databases such as PubMed, Google Scholar, Science Direct, and Medline. The analysis, performed using Review Manager Version 5.4.1 and Stata version 14.1, included a total of 24,979 T2DM cases and 33,005 controls. Employing fixed-effects or random-effects models, the combined Odds Ratio (OR) and 95% Confidence Intervals (CIs) were calculated to quantify the connection's magnitude. In the overall population, all genotypic models revealed a statistically noteworthy connotation between ENPP1 and T2DM (P < 0.05). Notably, the homozygous model exhibited an OR of 1.53 (95% CI = 1.23-1.90, P = 0.0001), while the heterozygous, dominant, recessive, and allelic models showed ORs of 1.22 (95% CI = 1.08-1.37, P = 0.001), 1.15 (95% CI = 1.11-1.41, P = 0.0003), 1.38 (95% CI = 1.17-1.64, P = 0.0002), and 1.22 (95% CI = 1.10-1.36, P = 0.0003), correspondingly. Subgroup analysis by population indicated no significant correlation between the K121Q polymorphism and T2DM in the African population, while a noteworthy association was detected in both Asian and Caucasian populations, with the heterozygous model lacking significance in the latter. Despite no evidence of publication bias, a notable amount of residual heterogeneity among studies was identified. Sensitivity analysis established the steadiness and dependability of the meta-analysis findings, underscoring the complex nature of the ENPP1 gene's involvement in T2DM across diverse populations.

Role of ENPP1 Gene Variants in the Susceptibility to Diabetic Nephropathy in Patients with type 2 Diabetes Mellitus.

Genetic factors are known to play a significant role in the susceptibility of diabetic patients to severe complications such as diabetic nephropathy (DN). This study aimed to evaluate the association between polymorphism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) variants (rs997509, K121Q, rs1799774, and rs7754561) and DN in patients with type 2 diabetes mellitus (T2DM). A total number of 492 patients with T2DM with and without DN were categorized into case and control groups. The extracted DNA samples were genotyped using TaqMan allelic discrimination assay amplified by polymerase chain reaction (PCR). The haplotype analysis among the case and control groups was performed using an expectation-maximization algorithm by the maximum-likelihood method. The analysis of laboratory findings demonstrated significant differences in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) between the case and control groups (P < 0.05). The results showed that K121Q was significantly related to DN under a recessive model of inheritance (P = 0.006); however, rs1799774 and rs7754561 both were protective for DN under a dominant model of inheritance (P = 0.034 and P = 0.010, respectively) among four studied variants. Two haplotypes, including C-C-delT-G with a frequency < 0.02 and T-A-delT-G with a frequency < 0.01, were associated with the increased risk of DN (P < 0.05). The present study demonstrated that K121Q was associated with the susceptibility of DN; however, rs1799774 and rs7754561 were protecrtive variants for DN in patients with T2DM.

PSAT219 Renal Phosphate Wasting Caused by ENPP-1 mutation.

Abstract Background Increased renal phosphate loss can be Fibroblast Growth Factor-23 (FGF-23) dependent or independent. FGF-23 reduces expression of Sodium-Phosphate co-transporters, responsible for phosphate reabsorption; and by inhibition of 1-alpha hydroxylation of 25-OH-D3. Reduced serum concentration of 1, 25-OH2-D3 results in secondary hyperparathyroidism. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) mutation is one of the rarest causes of hypophosphatemia, which causes FGF-23 dependent hypophosphatemia. Case description 31-year-old female referred to endocrinology for evaluation of recurrent nephrolithiasis despite normalization of PTH and serum Calcium (Ca) after right inferior parathyroid adenoma resection. Repeated renal stone analysis revealed calcium phosphate as the major stone composition. Patient achieved mid parental height, denied history of calcium or phosphate metabolism disorders/ rickets in the family. Physical exam was not suggestive of rickets and skeletal survey showed normal bone mineralization. Initial labs following parathyroid adenoma resection showed normal Ca 9.7 mg/dl, PTH 47 pg/ml, Phosphorus (Ph) 2.3 mg/dl, 25-OH-D3 51 ng/ml, albumin 3.9 g/dl, Mg 1.8 mg/dl. Repeat fasting labs six months later revealed Ca 9 mg/dl, Ph 1.7 mg/dl, 25-OH-D3 52 ng/ml, PTH 67.5 pg/ml and albumin 3.7 g/dl. Persistent low serum phosphate was evaluated further by a 24-hour urine collection which revealed high urine phosphate of 828 mg/day, Ca 181 mg/day, Mg 23 mg/day and creatinine was 1485 mg/day. Tubular reabsorption of phosphorus was 77% (normal: &amp;gt;80%), indicating renal phosphate wasting. Serum FGF-23 on two different days was &amp;gt;180 RU/ml. Next-generation sequencing tested positive for heterozygous ENPP-1 gene mutation variant c1441C&amp;gt;T (p. Arg481Trp). Patient was started on oral Phosphorus supplementation &amp; calcitriol. Repeat labs showed normalization of Ph 2.4 mg/dl. Audiology evaluation suggested mild sensorineural hearing loss. Heart calcium score was zero. Discussion ENPP1 gene mutation's clinical presentations can vary from no symptoms, hypophosphatemic rickets to death in the first six months of life from generalized arterial calcification. ENPP1 is an enzyme, which degrades ATP into adenosine monophosphate (AMP) and pyrophosphate (PPi). PPI is an inhibitor of hydroxyapatite crystallization in vascular tissue and organs, while Ph is a pro-mineralization factor. ENPP1 gene mutation results in a low concentration of PPi, predisposing the patient to pathological calcification. It is speculated that ENPP-1 modulates FGF-23 secretion. FGF-23 elevation in these patients is a protective response, as hypophosphatemia prevents pathological calcification. Treatment target is to keep phosphate at low end of normal. In our patient, ENPP- 1 mutation likely contributed to recurrent renal stones and possible parathyroid adenoma. Evaluation of genetic mutations is necessary to decide for or against FGF-23 antibody/Burosumab treatment. In ENPP-1 mutation. Burosumab should be avoided as it can bind to FGF-23 resulting in pathological calcification. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

K121Q polymorphism in the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 gene is associated with acute kidney rejection.

The identification of risk factors for acute rejection (AR) may lead to strategies to improve success of kidney transplantation. Ectonucleotidases are ectoenzymes that hydrolyze extracellular nucleotides into nucleosides, modulating the purinergic signaling. Some members of the Ectonucleotidase family have been linked to transplant rejection processes. However, the association of Ectonucleotide Pyrophosphatase / Phosphodiesterase 1 (ENPP1) with AR has not yet been evaluated. The aim of this study was to evaluate the association between the K121Q polymorphism of ENPP1 gene and AR in kidney transplant patients. We analyzed 449 subjects without AR and 98 with AR from a retrospective cohort of kidney transplant patients from Southern Brazil. K121Q polymorphism was genotyped using allelic discrimination-real-time PCR. Cox regression analysis was used to evaluate freedom of AR in kidney transplant patients according to genotypes. Q allele frequency was 17.6% in recipients without AR and 21.9% in those with AR (P = 0.209). Genotype frequencies of the K121Q polymorphism were in Hardy-Weinberg equilibrium in non-AR patients (P = 0.70). The Q/Q genotype (recessive model) was associated with AR (HR = 2.83, 95% CI 1.08–7.45; P = 0.034) after adjusting for confounders factors. Our findings suggest a novel association between the ENPP1 121Q/Q genotype and AR in kidney transplant recipients.

ENPP1 K121Q (rs1044498 C > A) genetic polymorphism confers a high risk of susceptibility to coronary heart disease: A PRISMA-compliant article.

Background:Previous studies suggested an association between K121Q (rs1044498 C > A) in ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene and the risk of coronary heart disease (CHD), but the results have been inconsistent. In this study, we performed a meta-analysis of several trials to systematically summarize their potential association.Methods:Relevant articles were identified by searching electronic databases for studies published prior to March 2018. We carefully reviewed published studies on ENPP1 genetic polymorphism in relation to CHD susceptibility. The data extracted from selected high-quality studies were analyzed using STATA statistical software (StataCorp LP, College Station, TX, USA).Results:Nine eligible studies which contained a combined total of 1547 CHD cases and 2213 healthy controls were chosen in the present meta-analysis. Our results indicated that K121Q strongly correlated with increased risk of CHD. The subgroup analysis on race, sample source, disease type, sex, age, and genotype showed that in Caucasians, K121Q strongly correlated with increased risk of CHD, but no difference was found in Chinese. Both single factor and multiple factor regression showed that race, sample origin, disease type, sex, age, and genotype were not the source of heterogeneity.Conclusions:Our meta-analysis revealed that the K121Q (rs1044498 C > A) in the ENPP1 gene is a risk factor for CHD.

Hypercementosis Associated with ENPP1 Mutations and GACI

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).

A case-control association study of K121Q (rs 1044498) and G/T (rs 1225572) variants in ENPP1 and TCF7L2 genes with type 2 diabetes mellitus in north Indian Punjabi population

Recently, the transcription factor-7-like 2 (TCF7L2) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) genes have been identified to have a significant functional role in determining susceptibility to type 2 diabetes. The purpose of this study was to confirm the reported association between K121Q and G/T polymorphisms of the ENPP1 and TCF7L2 genes, respectively with increased risk of type 2 diabetes mellitus in north Indian Punjabi population. A total of 450 participants consisting of 239 type 2 diabetes mellitus (T2DM) and 211 healthy subjects were recruited for this study. Genotyping was performed by PCR-RFLP method. Anthropometric and physiometric variables such as height, weight, body mass index (BMI), waist to hip ratio (WHR), waist circumference (WC), hip circumference (HC), biceps skinfold, triceps skinfold, SBP, DBP, MBP, pulse rate and pulse pressure were measured using standard protocol. The chi-square analyses were used to test the significant difference in genotype, allele frequencies and Hardy-Weinberg equilibrium deviation. Associations of genotypes with T2DM and its corresponding p values were calculated using logistic regression. The results revealed that anthropometric and clinical characteristics such as WHR, fasting and random glucose levels, SBP, DBP, pulse rate and pulse pressure have significant (p < 0.001) differences between T2DM and control subjects. However, none of the anthropometric and clinical characteristics have found a significant difference with respect to their genotypic distributions for both of genes except DBP for ENPP1 K121Q polymorphism. The distributions of frequencies of Q allele of rs 1044498 (K121Q) and T allele of rs 1225572 (G/T) polymorphism of ENPP1 and TCF7L2 genes were higher in T2DM patient patients but differences were not statistically significant. The association analysis of the present results showed K121Q variant of ENPP1 gene and G/T variant of TCF7L2 gene have a significant association with type 2 diabetes with dominant and recessive model of action, respectively, in north Indian Punjabi populations.

Liver ENPP1 protein increases with remission of type 2 diabetes after gastric bypass surgery.

BackgroundType 2 diabetes mellitus (T2DM) is a progressive disease resulting from increasing insulin resistance and reduced pancreatic β-cell insulin secretion. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibits insulin signalling and may contribute to the pathogenesis of T2DM. Others have found elevated ENPP1 levels in muscle, fat, and skin tissues from insulin resistant individuals, but similar data on liver ENPP1 is lacking. The purpose of this study was to compare expression and protein concentrations of ENPP1 in liver between patients with and without T2DM.MethodsRoux-en-Y gastric bypass surgery (RYGB) results in remission of insulin resistance and T2DM thus presenting an opportunity to examine some critical aspects of these conditions. We measured liver ENPP1 gene and protein expression in individuals with or without T2DM at RYGB and on average 17 (±5.6) months later.ResultsWe found liver ENPP1 protein abundance was lower in individuals with T2DM than in those with normal glucose tolerance, and increased after RYGB surgery in those individuals who had remission of T2DM. ENPP1 positively correlated with insulin sensitivity at the liver (as measured by HOMA-IR), which is contrary to what others have reported in other insulin target tissues.ConclusionsLiver ENPP1 expression in T2DM is the reverse of that expected based on expression in other tissues and is likely due to the unique role the liver has in insulin clearance. The work presented here adds another dimension to the role of ENPP1, and supports the hypothesis that ENPP1 may act as a natural modulator of insulin signalling in the liver.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-014-0222-x) contains supplementary material, which is available to authorized users.

K121Q Polymorphism of the &lt;i&gt;ENPP1&lt;/i&gt; Gene is Related to Acute Coronary Syndrome in Ukrainian Patients with Normal but not Enhanced Body Mass Index

Ectonucleotide Pyrophosphatase Phosphodiesterase 1 (ENPP1) is a class II membrane glycoprotein with two unrelated properties: It can hydrolyze extracellular nucleotides and downregulate insulin receptor signaling. The present study was carried out to investigate whether common single-nucleotide polymorphism K121Q (rs1044498) of the ENPP1 gene is associated with Acute Coronary Syndrome (ACS) in the representatives of Ukrainian population and to assess if the risk depends on gender and Body Mass Index (BMI). A total 228 DNA samples (118 ACS patients and 110 control subjects) were genotyped for the polymorphism by PCR and restriction fragment length polymorphism method. No associations between the K121Q polymorphisms and ACS were found neither on the whole nor taking into account the gender. However, in the persons with BMI

Intermittent Cyclic Mechanical Tension‐induced Down‐regulation of Ectonucleotide Pyrophosphatase Phosphodiesterase 1 Gene Expression is Mainly Dependent on TGF‐β1 in End‐plate Chondrocytes

To investigate the relationship between ectonucleotide pyrophosphatase phosphodiesterase-1(ENPP-1) expression and transforming growth factor beta 1 (TGF-β1) of end-plate chondrocytes after stimulation with intermittent cyclic mechanical tension (ICMT) by using an FX-4000T Flexercell Tension Plus unit. Rat end-plate chondrocytes were cultured and ICMT (strain at 0.5 Hz sinusoidal curve at 10% elongation) applied for 7 days for 4 h/day and cultured for a further 2 days. End-plate chondrocytes were also exposed to 10 ng/mL of TGF-β1. Then, using small interfering RNA technology, small interfering TGF-β1 (siTGF-β1) was transfected. Expression of ENPP-1 and TGF-β1 was measured by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and western blotting. Expression of both ENPP-1 and TGF-β1 was up-regulated after ICMT. Both RT-PCR and western blot showed that ENPP-1 expression decreases with siRNA TGF-β1 after 3% elongation 40 min, and cultured for an additional 2 days. It was found that down-regulation of ENPP-1 gene expression induced by ICMT is likely dependent on TGF-β1 in end-plate chondrocytes.

Genetic determinants and early carotid atherosclerosis: is there a role for the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP-1) K121Q polymorphism? Preliminary results in non diabetic individuals

Carotid intima-media thickness (CIMT) is an intermediate phenotype for early atherosclerosis and a strong predictor of myocardial infarction and ischemic stroke [1]. Several studies have described the effects of candidate genes on CIMT, being unclear, however, the relative contribution of genetic variation to the development of the early stages of atherosclerosis [2]. The ectoenzyme pyrophosphatase phosphodiesterase 1 (ENPP-1) inhibits insulin receptor signaling [3]. A non synonymous polymorphism (K121Q, rs1044498) of the ENPP-1 gene is responsible for a gain of function of the protein [3], resulting in an increased ability to inhibit insulin receptor signaling. This variant has been associated with insulin resistance and type 2 diabetes in most studies [4, 5]. In agreement with the link between insulin resistance and cardiovascular disease (CVD), the Q121 variant has been shown to modulate susceptibility to premature myocardial infarction [6] and ischemic stroke [7] and to increase pulse pressure, a marker of arterial stiffness [8]. Some of these associations have been shown to be stronger in obese subjects, suggesting a gene-byobesity interaction in facilitating insulin resistance and atherogenic process [4, 9]. Up to date no results on ENPP-1 function on CIMT are available. Thus, we tested whether the ENPP-1 Q121 variant exerts an effect on CIMT measured at the common carotid artery (CCA) and at bulb and interacts with overweight–obesity in modulating CIMT.

The role of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 in diabetic nephropathy

The increased prevalence of diabetes mellitus has caused a rise in the occurrence of its chronic complications, such as diabetic nephropathy (DN), which is associated with elevated morbidity and mortality. Familial aggregation studies have demonstrated that besides the known environmental risk factors, DN has a major genetic component. Therefore, it is necessary to identify genes associated with risk for or protection against DN. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. Increased levels of ENPP1 expression inhibit tyrosine-kinase activity of the insulin receptor in several cell types, leading to insulin resistance. K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. The elucidation of genetic factors and their associations will provide better understanding of the pathogenesis of DN and, may consequently, lead to a more effective approach to prevention and treatment.

A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene

X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets/osteomalacia (ARHR1 or ARHR2) are hereditary fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets showing similar clinical features. We here show a patient with hypophosphatemic rickets and widespread ossification of posterior longitudinal ligament (OPLL). The proband is a 62-year-old female. Her parents are first cousins and showed no signs of rickets or osteomalacia. She showed hypophosphatemic rickets with elevated FGF23 level and had been clinically considered to be suffering from XLH. However, direct sequencing of all coding exons and exon-intron junctions of phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX), FGF23 and dentin matrix protein 1 (DMP1) genes, responsible genes for XLH, ADHR and ARHR1, respectively, showed no mutation. A novel homozygous splice donor site mutation was found at the exon-intron junction of exon 21 of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene responsible for ARHR2 (IVS21+1_3(GTA>CACC)). Subsequent analysis of mRNA revealed that this mutation caused skipping of exon 21 which created a premature stop codon in exon 22. These results indicate that genetic analysis is mandatory for the correct diagnosis of hereditary FGF23-related hypophosphatemic rickets. Because Enpp1 knockout mouse is a model of OPLL, this case also suggests that OPLL is associated with ARHR2.

Insulin resistance and left ventricular hypertrophy in end-stage renal disease: association between the ENPP1 gene and left ventricular concentric remodelling

Left ventricular hypertrophy (LVH) and insulin resistance (IR) are frequent complications of end-stage renal disease (ESRD). The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene, whose variability has been repeatedly associated with IR, codes for a membrane glycoprotein which inhibits insulin-receptor signalling. We investigated the relationship of ENPP1 variability, as indicated by 10 single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure, with left ventricular mass and geometry (by echocardiography) in an ethnically homogeneous series of 238 Caucasian ESRD patients. ENPP1 rs1974201 and rs9402349 polymorphisms were coherently associated (P ranging from 0.04 to 0.005) with indicators of left ventricular (LV) myocardial hypertrophy (mean wall thickness) and concentric remodelling (relative wall thickness and LV mass-to-volume ratio) but unrelated with the cavitary component of the LV (left ventricular end-diastolic volume). As compared to individuals carrying the alternative genotypes, the risk of LV concentric remodelling was approximately doubled in major allele homozygous for rs1974201 [odds ratio (OR) of GG versus GC + CC: 2.31, 95% confidence interval (CI): 1.30-4.12, P = 0.004] and rs9402349 (OR of AA versus AC + CC: 1.91, 95% CI: 1.02-3.56, P = 0.04) polymorphisms. Coherent associations exists between echocardiographic parameters of LV myocardial hypertrophy and concentric remodelling and ENPP1 variability in ESRD patients. These data support the hypothesis that IR is a relevant factor in the pathogenesis of myocardiopathy in this population.

Autosomal-Recessive Hypophosphatemic Rickets Is Associated with an Inactivation Mutation in the ENPP1 Gene

Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1.

Polimorfismo K121Q do gene ENPP1 e cardiopatia isquêmica em pacientes com diabete melito

The ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene is a candidate gene for insulin resistance. Insulin resistance is a major component of metabolic syndrome (MetS) and has been implicated in ischemic heart disease (IHD).To evaluate the association between the K121Q polymorphism of the ENPP1 gene and IHD in white patients with type 2 diabetes mellitus (DM).A cross-sectional study was performed in type 2 DM patients (n = 573, 50.6% males, age 59.5+/-10.4 years). IHD was defined by the presence of angina or myocardial infarction according to the Worth Health Organization cardiovascular questionnaire and/or compatible electrocardiographic (Minnesota Code), or perfusional abnormalities in myocardial scintigraphy. The K121Q polymorphism of ENPP1 gene was genotyped using PCR-based methods and restriction enzyme digestion.IHD was present in 209 (36.5%) patients. The distribution of KK, KQ and QQ genotypes among patients with IHD was 60.8%, 34.4% and 4.8%, not different from the genotype distribution in the group without IHD (64%, 32.7% and 3.3%, P=0.574). No difference was found in the clinical and laboratory characteristics between the three genotypes, neither regarding the prevalence of Metabolic Syndrome.No association was found between polymorphism K121A of ENPP1 gene and the presence of IHD.

Impact of ENPP1 and MMP3 gene polymorphisms on aortic calcification in patients with type 2 diabetes in a Korean population

Aims We investigated whether gene polymorphisms of Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1) and matrix metalloproteinase 3 ( MMP3) are associated with increased vascular calcification in patients with type 2 diabetes (T2D) and evaluated whether serum MMP3 and osteoprotegerin (OPG) levels are related to calcification. Methods This study included 464 subjects: 269 patients with T2D and 195 healthy controls in South Korea. We genotyped subjects for four single nucleotide polymorphisms (SNPs): ENPP1 K121Q, ENPP1 A/G+1044TGA, MMP3 −709A>G and MMP3 −1475G>A. The presence or absence of calcifications in the aortic arch was assessed by plain chest radiography. Results The SNPs ENPP1 K121Q and MMP3 −709A>G showed significant associations with T2D ( P = 0.001 and P = 0.004). The SNP ENPP1 K121Q showed a significant association with aortic arch calcification in T2D ( P = 0.036). Serum OPG levels were significantly higher in T2D patients than in the control group ( P < 0.001). However, serum MMP3 levels were significantly lower in T2D patients than in the control group ( P < 0.001). Conclusions Our study demonstrates that the ENPP1 K121Q and MMP3 −709A>G polymorphisms are associated with T2D, and that the ENPP1 Q allele is associated with increased aortic arch calcification in a Korean population.

Fetal Hydrops, Hyperechogenic Arteries and Pathological Doppler Findings at 29 Weeks: Prenatal Presentation of Generalized Arterial Calcification of Infancy – A Novel Mutation in ENPP1

Prenatal diagnosis of generalized arterial calcification of infancy (GACI) (OMIM #208000) is difficult and rare. There are various known gene mutations in ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) locus 6q22-q23. We present a case of suspected intrauterine diagnosis at 29 weeks of gestation in a consanguineous couple. The sonographic findings were fetal hydrops (hydrothorax, skin edema, ascites, pericardial effusion and polyhydramnion), echogenic great arteries and pathological Doppler findings. An intrauterine therapy with bisphosphonates was considered, but delayed due to rapid deterioration in fetal Doppler flows with suspected fetal asphyxia. The couple was informed about the most unfavorable prognosis in fetal hydrops, however, they opted for elective delivery. A cesarean section was performed. Early neonatal death occurred due to primary intracranial hemorrhage. Postmortem and genetic testing confirmed a novel mutation in the ENPP1 gene.

Haplotype structure of the ENPP1 Gene and Nominal Association of the K121Q missense single nucleotide polymorphism with glycemic traits in the Framingham Heart Study.

OBJECTIVE—A recent meta-analysis demonstrated a nominal association of the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K→Q missense single nucleotide polymorphism (SNP) at position 121 with type 2 diabetes. We set out to confirm the association of ENPP1 K121Q with hyperglycemia, expand this association to insulin resistance traits, and determine whether the association stems from K121Q or another variant in linkage disequilibrium with it.RESEARCH DESIGN AND METHODS—We characterized the haplotype structure of ENPP1 and selected 39 tag SNPs that captured 96% of common variation in the region (minor allele frequency ≥5%) with an r2 value ≥0.80. We genotyped the SNPs in 2,511 Framingham Heart Study participants and used age- and sex-adjusted linear mixed effects (LME) models to test for association with quantitative metabolic traits. We also examined whether interaction between K121Q and BMI affected glycemic trait levels.RESULTS—The Q allele of K121Q (rs1044498) was associated with increased fasting plasma glucose (FPG), A1C, fasting insulin, and insulin resistance by homeostasis model assessment (HOMA-IR; all P = 0.01–0.006). Two noncoding SNPs (rs7775386 and rs7773477) demonstrated similar associations, but LME models indicated that their effects were not independent from K121Q. We found no association of K121Q with obesity, but interaction models suggested that the effect of the Q allele on FPG and HOMA-IR was stronger in those with a higher BMI (P = 0.008 and 0.01 for interaction, respectively).CONCLUSIONS—The Q allele of ENPP1 K121Q is associated with hyperglycemia and insulin resistance in whites. We found an adiposity-SNP interaction, with a stronger association of K121Q with diabetes-related quantitative traits in people with a higher BMI.

The K121Q polymorphism of ENPP1 and peripheral arterial disease

The K121Q variant of the ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) gene is associated with obesity, insulin resistance, and early myocardial infarction. Therefore, we hypothesized that the K121Q polymorphism might also be associated with an increased risk for peripheral arterial disease. Four hundred patients with peripheral arterial disease and 400 controls matched for sex and age (+/- 2 years) were genotyped cross-sectionally for the K121Q single nucleotide polymorphism of the ENPP1 gene. The frequency for the 121Q allele was 0.25 both in patients with peripheral arterial disease and in controls (P = 0.75). Subgroup analysis revealed association of the ENPP1 121QQ genotype with higher glycohemoglobin A1C levels (P = 0.001) and earlier onset of peripheral arterial disease (P = 0.003) in the cohort of nonsmokers. Whereas the K121Q genotype of the ENPP1 gene is not associated with presence of peripheral arterial disease in the whole Linz Peripheral Arterial Disease population, it is associated with type 2 diabetes mellitus and earlier onset of peripheral arterial disease in the subgroup of nonsmoking patients.