Ectoenzyme Nucleotide Pyrophosphate Phosphodiesterase Research Articles

The ENPP1 K121Q polymorphism is associated with obesity-related parameters in Iranian normoglycemic male subjects

Objectives: The K121Q polymorphism of the Ectoenzyme Nucleotide Pyrophosphate Phosphodiesterase 1 (ENPP1) gene has been variably associated with obesity in several populations. However, this association has not been studied in Iranian subjects. It was hypothesized that the K121Q variant might be associated with obesity and related risk factors in subjects with normal glucose tolerance and normal fasting glucose.
 Methods: The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 non-diabetic subjects.
 Results: In males, the frequency of the Q allele was 20.8% and 15.9% (p=0.269) in obese and non-obese subjects, respectively. The ENPP1 genotype (KQ+QQ) was not associated with systolic and diastolic blood pressure, triglyceride, cholesterol, LDL-C, HDL-C, HOMA-IR, or insulin levels in both genders. Male carriers of the KQ+QQ genotype had significantly higher values for BMI (p=0.079), waist (p=0.01), and WHR (p=0.006) than subjects with the KK genotype. Obesity-related parameters were not significantly different between obese and non-obese female subjects.
 Conclusion: Our results suggest that the ENPP1 121Q allele might be associated with obesity and related parameters only among Iranian normoglycemic male subjects.

New Insights Regarding Genetic Aspects of Childhood Obesity: A Minireview.

Introduction: Childhood obesity is occurring at alarming rates in both developed and developing countries. “Obesogenic” environmental factors must be associated with variants of different risk alleles to determine polygenic or common obesity, and their impact depends on different developmental stages.The interaction between obesogenic environment and genetic susceptibility results in the so-called polygenic forms of obesity. In contrast, monogenic and syndromic obesity are not influenced by environmental events. Therefore, this review aimed to underline the roles of some of the most studied genes in the development of monogenic and polygenic obesity in children.Results: Among the most common obesity related genes, we chose the fat mass and obesity-associated (FTO) gene, leptin gene and its receptor, tumor necrosis factor alpha (TNF-α), the melanocortin 4 receptor gene (MC4R), Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1), and others, such as peroxisome proliferator-activated receptor gamma (PPARG), angiotensin-converting enzyme (ACE), glutathione S-transferase (GST), and interleukin-6 (IL-6) genes. The roles of these genes are complex and interdependent, being linked to different cornerstones in obesity development, such as appetite behavior, control of food intake and energy balance, insulin signaling, lipid and glucose metabolism, metabolic disorders, adipocyte differentiation, and so on.Conclusions: Genetic predisposition is mandatory, but not enough to trigger obesity.Dietary interventions and proper lifestyle changes can prevent obesity development in genetically predisposed children. Further studies are needed to identify the precise role of both genetic and obesogenic factors in the development of childhood obesity in order to design effective preventive methods.

Association of the ENPP1 K121Q polymorphism with susceptibility to type 2 diabetes in different populations: evidence based on 40 studies.

The K121Q gene polymorphism of ectoenzyme nucleotide pyrophosphate phosphodiesterase 1(ENPP1) has been widely investigated, however, results have been somewhat conflicting. The aim of this meta-analysis was to establish a precise estimation of the association between ENPP1 gene polymorphisms and type 2 diabetes (T2D). A literature search in PubMed, Embase, Cochrane Library and China Biology Medicine (CBM) databases was conducted on publications published prior to November 21(st), 2013. The combined odds ratio (OR) with 95% confidence intervals (95% CI) was calculated to estimate the strength of the association using a random-effects/fixed-effects model. Statistical analyses were performed using the STATA 11.0 software. For the overall population, there was a significant association between ENPP1 gene polymorphisms and T2D when comparing the Q allele versus K allele (OR = 1.29, 95% CI 1.16-1.44, p = 0.000). Considering diverse ethnic groups, effect sizes were consistent for patients of Caucasian and Asian descent (OR = 1.20, 95% CI = 1.08-1.33 and OR = 1.47, 95% CI = 1.15-1.89, respectively); however, effect size was not consistent for those of African descent. Under other models of inheritance, significant associations were also observed. Sensitivity analyses did not leading to differing he results. In summary, the Q allele of the ENPP1 K121Q gene may contribute to the susceptibility for T2D in Caucasians and Asians.

Impact of ENPP1 K121Q on change of insulin resistance after web-based intervention in Korean men with diabetes and impaired fasting glucose.

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to type 2 diabetes mellitus (T2DM) and insulin resistance (IR). We hypothesized that the difference in genotype may be one of the factors that affect the outcome of intervention. We genotyped 448 men with fasting glucose≥5.6 mM/L, including 371 in subjects with K allele (KK) (69 control group [CG]; and 302 intervention group [IG]) and 77 in subjects with Q allele (KQ+QQ) (13 CG and 64 IG). The web-based intervention based on a lifestyle modification was delivered by e-mail once a month for 10 months. In the KK, IG demonstrated significantly decreased levels of fasting serum insulin (FSI) as compared to CG and homeostasis model of assessment of insulin resistance (HOMA-IR). In the KQ+QQ IG group, hemoglobin A1c (HbA1c), FSI and HOMA-IR were significantly decreased, and showed further reduction in the HOMA-IR than KQ+QQ CG. After analysis of covariance, K121Q did significantly influence the change of HbA1c in CG after appropriate adjustment. In a multivariate model, BMI change predicted HOMA-IR change (adjusted β=0.801; P=0.022) in KK IG subjects with T2DM. ENPP1 K121Q did not influence the change in IR. However, individuals with T2DM carrying the K121 variant are very responsive to the effect of BMI reduction on HOMA-IR.

ENPP1 K121Q polymorphism and type 2 diabetes mellitus in the Chinese population: a meta-analysis including 11 855 subjects

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) K121Q gene polymorphism has been suggested to be associated with the increased risk of developing type 2 diabetes mellitus (T2D), but relevant research results are still contradictory. To explore the relationship between ENPP1 K121Q gene polymorphism and T2D in the Chinese population, a meta-analysis was performed. Fourteen independent studies involving 11 855 subjects were retrieved from electronic databases. The pooled odds ratio (ORs) for the distribution of Q allele frequency of the ENPP1 K121Q gene and its corresponding 95% confidence interval (95% CI) were assessed using a random-effects model. Under an allelic model of inheritance, the distribution of Q allele frequency was 0.107 for the T2D group and 0.093 for the control group. The pooled OR for the distribution of Q allele frequency of ENPP1 K121Q gene was 1.29 (95% CI, 1.09-1.53; Pheterogeneity = .006; I2 = 55.6%). There was a significant association between ENPP1 K121Q gene polymorphism and T2D in the Chinese population (P = .003). Under a dominant model of inheritance, the KQ + QQ/KK value was 0.259 for the T2D group and 0.220 for the control group. The pooled OR for the KQ + QQ/KK value was 1.51 (95% CI, 1.20-1.91; Pheterogeneity < .0001; I2 = 71.8%). The association between ENPP1 K121Q gene polymorphism and T2D in the Chinese population followed a dominant model of inheritance (P = .0005). In the Chinese population, the ENPP1 K121Q gene polymorphism was implied to be involved with T2D susceptibility. People with the Q allele of the ENPP1 K121Q gene might be predisposed to T2D.

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes in northern Chinese

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to insulin resistance, type 2 diabetes, and obesity, and conflicting results were observed in various populations. The purpose of the present study was to investigate the prevalence of K121Q polymorphism of ENPP1 gene and to clarify whether this polymorphism is associated with type 2 diabetes susceptibility in northern Chinese population. We studied the association of the ENPP1 K121Q polymorphism with type 2 diabetes (T2D) in 639 unrelated patients and 885 control subjects with normal glucose tolerance of northern China. The patients were diagnosed in accordance with the guidelines of the American Diabetes Association (ADA). Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The distribution of KK, KQ, and QQ genotypes among patients was 79.5, 19.2, and 1.3%, similar to that of the control group (79.2, 20.1, and 0.7%). After readjusting for the confounding effects of age, gender, and BMI, no significant effect of genotypes on T2D was found for any of the genetic models tested (recessive model, dominant model, or additive model). All clinical characteristics tested were similar among the different genotypes, and no significant associations were observed both in T2D patients and in controls. When subgroup analyses of T2D patients and non-diabetic controls were stratified according to BMI and waist circumference, the variant was still not associated with T2D. The results showed that the ENPP1 K121Q polymorphism is not associated with genetic susceptibility of type 2 diabetes in the northern Chinese population.

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes and related metabolic traits in an Iranian population

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been variably associated with insulin resistance and type 2 diabetes (T2D) in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that the K121Q variant might be associated with T2D and related metabolic traits in this population. The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 normoglycemic controls and 155 T2D patients. T2D patients had significantly higher values for systolic and diastolic blood pressure, BMI, glucose, cholesterol, triglyceride, LDL, apoB, insulin, and HOMA-IR, and lower levels of HDL than the normoglycemic subjects. The frequency of the Q allele did not differ between T2D and normoglycemic subjects (OR 0.96, 95% CI 0.90-2.00, P=0.70). The Q allele frequency was 16.5% in T2D and 15.2% in normoglycemic subjects. The ENPP1 genotype (KQ+QQ) was not associated with the systolic and diastolic blood pressure, glucose, triglyceride, cholesterol, LDL-C and HDL-C, apo B, BMI, HOMA-IR, and insulin levels in both normoglycemic and T2D groups. Our results suggest that the ENPP1 121Q allele might not be associated with T2D and related metabolic traits among Iranian subjects.

ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes in North Indians

Genetic susceptibility may be responsible for high prevalence of type 2 diabetes worldwide. A common missense single nucleotide polymorphism, K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene, has recently been associated with type 2 diabetes in Italian, South Indian, and American populations. The objective of this study was to investigate the possible role of K121Q polymorphism in ENPP1 gene with type 2 diabetes in North Indians. The genotype of the ENPP1/PC-1 K121Q polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism analysis for 328 T2DM patients and 326 non-diabetic participants. Anthropometric and clinical characteristics (Body mass index (BMI), glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), Creatinine, HbA1c, and insulin levels) were measured using standard protocols. Their Chi-square analyses were used to test the significance differences in genotypic and allelic frequencies. Association studies were undertaken using the t test and logistic regression analyses. Our results revealed there was no significant difference in the genotypic distribution between T2DM patients and control subjects. The KK and KQ genotype frequencies were similar in T2DM cases and controls (60.7 and 39.3% in T2DM and 59.8 and 40.2% in controls). No subjects with the QQ genotype were found. Binary logistic regression analysis of data did not show any association of K121Q polymorphism with type 2 diabetes (OR; 0.97, 95% CI; 0.7-1.32, P=0.82). No significant correlation among the BMI, WHR, BP, TG, TC, HDL-C, LDL-C, Glucose, HbA1c, Creatinine, and insulin indices (HOMA-IR) was observed in the individuals carrying KK and KQ genotypes. In conclusion, our results showed that ENPP1/PC-1 K121Q polymorphism is not associated with type 2 diabetes and related quantitative metabolic traits in North Indian Punjabi population.

Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease

Background/aimsThe aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity...

Genetic Polymorphism of Ectoenzyme Nucleotide Pyrophosphate Phosphodiesterase (ENPP1) and Susceptibility to Type 2 DM and Its Complications

BackgroundA functional missense DNA polymorphism in exon 4 of ENPP1 gene causes amino acid change from lysine to glutamine at codon 121 (K121Q). The Q variant of PC1 is associated with reduction of insulin receptor autophosphorylation and therefore a stronger inhibitor of insulin signaling.AimTo test the hypothesis that ENPP1 K121Q polymorphism is associated with type 2 DM and its complication.Methods167 normal individual, 30 non‐complicated type 2 diabetic patients and 76 complicated type 2 diabetic patients were enrolled in the study. The ENPP1 K121Q genotypes were identified by RFLP‐PCR of peripheral blood DNA samples. Analysis of data was done by using SPSS program.ResultsAllele frequency for Q was 36.8% in the diabetic group compared to 26% in the control group. The carriers of XQ genotype (KQ and QQ) were at high risk of developing type 2 DM (OR= 1.8; 95% CI = 1.1‐2.9) when compared with the carrier of KK genotype. Furthermore they were at much higher risk of developing its complications (OR= 2.1; 95% CI=0.9‐4.9).ConclusionQ 121 allele is a genetic determinant of type 2 DM and related atherogenic phenotypes.Source of research supportDubai Medical College for Girls

The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations

Functional studies suggest that the nonsynonymous K121Q polymorphism in the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) may confer susceptibility to insulin resistance; genetic evidence on its effect on type 2 diabetes, however, has been conflicting. We therefore conducted a new meta-analysis that includes novel unpublished data from the ENPP1 Consortium and recent negative findings from large association studies to address the contribution of K121Q to type 2 diabetes. After a systematic review of the literature, we evaluated the effect of ENPP1 K121Q on diabetes risk under three genetic models using a random-effects approach. Our primary analysis consisted of 30 studies comprising 15,801 case and 26,241 control subjects. Due to considerable heterogeneity and large differences in allele frequencies across populations, we limited our meta-analysis to those of self-reported European descent and, when available, included BMI as a covariate. We found a modest increase in risk of type 2 diabetes for QQ homozygotes in white populations (combined odds ratio [OR] 1.38 [95% CI 1.10-1.74], P = 0.005). There was no evidence of publication bias, but we noted significant residual heterogeneity among studies (P = 0.02). On meta-regression, 16% of the effect was accounted for by the mean BMI of control subjects. This association was stronger in studies in which control subjects were leaner but disappeared after adjustment for mean control BMI (combined OR 0.93 [95% CI 0.75-1.15], P = 0.50). The ENPP1 Q121 variant increases risk of type 2 diabetes under a recessive model of inheritance in whites, an effect that appears to be modulated by BMI.

No Evidence of Association of ENPP1 Variants With Type 2 Diabetes or Obesity in a Study of 8,089 U.K. Caucasians

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. There is strong evidence from several previous studies that a common coding variant of ENPP1 (K121Q) and a three-marker haplotype (Q121, IVS20delT-11, and G+1044TGA) are associated with type 2 diabetes and obesity. We examined the impact of ENPP1 variation on type 2 diabetes and obesity in a large U.K. genetic association study. We genotyped the three previously associated polymorphisms in 2,363 type 2 diabetic case and 4,045 control subjects, as well as 1,681 subjects from 529 type 2 diabetic families. We used the same subjects for morbid and moderate obesity association studies. For type 2 diabetes, moderate and morbid obesity, and for both the Q121 and three-marker haplotype, our results exclude with >95% confidence the effect sizes from previous studies (Q121 allele: odds ratio 1.02 [95% CI 0.93-1.12], P = 0.61; 1.00 [0.85-1.18], P = 0.99; and 0.92 [0.70-1.20], P = 0.41; three-marker haplotype: 1.10 [0.96-1.26], P = 0.17; 0.97 [0.77-1.23], P = 0.81; and 0.86 [0.57-1.30], P = 0.46 for type 2 diabetes, moderate, and morbid obesity, respectively). A K121Q type 2 diabetes meta-analysis of all previously published studies remained significant after the inclusion of this study (1.25 [1.10-1.43], P = 0.0007), although there was some evidence of publication bias. In conclusion, we find no evidence that previously associated variants of ENPP1 are associated with type 2 diabetes or obesity in the U.K. population.

Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity.

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78-0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.

ENPP1 K121Q Polymorphism is not Related to Type 2 Diabetes Mellitus, Features of Metabolic Syndrome, and Diabetic Cardiovascular Complications in a Chinese Population

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is known to influence insulin sensitivity by inhibiting insulin receptor signaling. A DNA polymorphism in the ENPP1 gene at exon 4 (K121Q) was demonstrated to be associated with insulin resistance, type 2 diabetes mellitus (T2DM), and a risk of early myocardial infarction, albeit with controversy. Our aim was to investigate any association of ENPP1 K121Q alleles with T2DM, features of the metabolic syndrome, and diabetic cardiovascular complications in a Chinese population of Han origin. The ENPP1 K121Q polymorphism was determined by a restriction fragment-length polymorphism-polymerase chain reaction in 1,862 patients with T2DM and 844 non-diabetic subjects. The genotype distributions or Q-allele frequency were not statistically different between the diabetic and non-diabetic groups. The anthropometric parameters, systolic and diastolic blood pressures, lipid profiles, and serum creatinine levels of subjects with different ENPP1 K121Q polymorphisms were not statistically different in the two groups or even in the pooled data. When sub-group analyses of diabetic subjects were stratified according to BMI levels (greater or less than 27), gender, age of diabetes onset (older or younger than 60 years), and the presence or absence of a diabetic family history; this polymorphism was still not associated with T2DM. Nor was the ENPP1 K121Q polymorphism associated with the prevalence of coronary artery disease and ischemic cerebrovascular disease in patients with T2DM. The ENPP1 K121Q polymorphism is not related to T2DM, features of the metabolic syndrome, or diabetic macrovascular complications in a Chinese population.