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Genotype distribution and minor allele frequency of ENPP1 K121Q among Danish patients with type 2 diabetes and glucose-tolerant and normoglycaemic subjects
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Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor alpha subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obe...
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The 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 on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic...
Genetic susceptibility may be responsible for high prevalence of insulin resistance in Asian Indians. This study was carried out in samples of local Asian Indians and Caucasians to determine whether plasma cell membrane glycoprotein (PC)-1 K121Q and insulin receptor substrate-1 (IRS-1) G972A polymorphisms contribute significantly to susceptibility...
To test for association of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q polymorphism with body mass index (BMI) and diabetes in a large sample of Caucasians and African-Americans by selectively genotyping individuals at the extremes of the phenotypic distribution.
Subsets comprising the extremes of the BMI distribution (10th...
The human glycoprotein PC-1 codon Q121 allele has been correlated with insulin resistance, but not with type 2 diabetes or obesity. We investigated the prevalence of PC-1 Q121 in the Dominican Republic population (755 subjects studied) and whether this variant is associated with insulin resistance, obesity, or type 2 diabetes. The prevalence of PC-...
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 as...
Citations
... The possible reason is that ENPP1 binds to the insulin receptor, impairs receptor function, reduces the signal cascade, and inhibits insulin signal transduction, resulting in insulin resistance. [28][29][30][31] Therefore, the concentration of ENPP1 in diabetic patients often increases significantly. In order to eliminate the interference of diabetic patients on the study, this study selected nondiabetic patients on dialysis, and the results are basically consistent with the conclusions of the above literatures. ...
Objective
To investigate the correlation between serum ectonucleotide pyrophosphatase/phosphodiesterase‐1 (ENPP1) level and severity of abdominal vascular calcification in end‐stage renal disease (ESRD) patients receiving dialysis.
Methods
A total of 124 patients were consecutively enrolled into the study in our local institution. Based on the Kidney Disease Improving Global Outcomes (KDIGO) guidelines and recommendations, abdomen lateral X‐ray was used to determine abdominal aortic calcification score (AACS) for each patient at enrollment. Patients were divided into three groups based on AACS: no or mild calcification group, moderate calcification group, and severe calcification group. The relationships between ENPP1 levels and AACS were assessed by Spearman analysis and the value of ENPP1 in predicting severity of abdominal aortic calcification was evaluated by receiver operating characteristic (ROC).
Results
The level of ENPP1 in dialysis patients was (7.68 ± 1.67) ng/ml. There was no significant difference in serum ENPP1 level between peritoneal dialysis patients and hemodialysis patients (p > 0.05). The AACS of dialysis patients was negatively correlated with ENPP1 value (r = −0.70). Compared to no/mild calcification patients, the levels of serum ENPP1 in patients with moderate/severe calcification were decreased significantly (p < 0.01). The severity of vascular calcification was correlated with serum ENPP1 value, the severer the vascular calcification, the lower the serum ENPP1 level, and the difference was statistically significant (all p < 0.05). The area under ROC curve of ENPP1 was 0.90, the corresponding sensitivity was 0.86, and the specificity was 0.87.
Conclusion
Levels of serum ENPP1 in non‐diabetic ESRD patients are negatively related to the severity of abdominal aortic vascular calcification.
... This polymorphism has been found to be associated with T2D in Korean (Lee et al. 2010), Chinese (Li 2012), Italian (Pizzuti et al. 1999;Bacci et al. 2005;Baratta et al. 2008), Iranian (Sharafshah et al. 2018), Ukrainian (Marchenko et al. 2018), and Taiwanese (Hsiao et al. 2016) populations. In contrast, other studies have not been able to replicate this positive association in North Indian (Bhatti et al. 2010), Chinese (Chen et al. 2006;Shi et al. 2011;Zhao et al. 2011), German (Gouni-Berthold et al. 2006, Iranian (Saberi et al. 2011), Korean (Seo et al. 2008, Japanese (Keshavarz et al. 2006), Tunisian (Ezzidi et al. 2009), Moroccan (El Achhab et al. 2009) and Danish (Grarup et al. 2006) populations. ...
Aim: To evaluate the influence of the K121Q variant in the ENPP1 gene on the risk of PCOS development and its associated traits of glucose tolerance, insulin resistance, hyperandrogenemia and dyslipidemia in Indian women. Methods: Genotyping of K121Q polymorphism of ENPP1 was performed in women with PCOS (N = 185) and controls (N =153) women, while phenotypic characterization in terms of clinical, biochemical and hormonal parameters was performed in 83 controls and 143 PCOS women. Genotype only and genotype-phenotype associations were determined by appropriate statistical tests. Results: The K121Q polymorphism showed comparable genotypic frequency distribution between controls and women with PCOS even after BMI-based classification. Intriguingly, both lean and obese controls showed significant association of polymorphic allele with decreased total testosterone levels. Amongst women with PCOS, this polymorphism was significantly associated with lowered LH levels and LH:FSH ratios in lean women, and reduced triglyceride levels in obese women only, respectively. Importantly, the Q allele was found to be significantly associated with increased risk of obesity in women with PCOS only. Conclusion: This is the first study to determine that even though the K121Q polymorphism of ENPP1 does not influence PCOS risk in Indian women, it beneficially impacts hyperandrogenemia, gonadotropin levels and dyslipidemia in women in accordance with their underlying obesity and physiological status. The contribution of the Q allele to elevated tendency towards obesity may aid clinicians in suggesting appropriate therapeutic interventions to avert long term cardiometabolic complications. This warrants deeper focus on the complex genetic pathomechanisms underlying PCOS. Citation: Shaikh N et al. The K121Q polymorphism of ENPP1 shows association with obesity in Indian women with PCOS. Polymorphism 2021; 7: 36-51.
... Another study in Denmark revealed that homozygous carriers of the QQ variant had a higher risk of being overweight, with OR 1.63 (95% CI, 1.09-2.46); however, there was no significant relationship between the presence of the Q variant and the development of type 2 diabetes or insulin resistance [29]. ...
Single nucleotide polymorphisms (SNPs) in obesity-related genes, such as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) and adiponectin (ADIPOQ), potentially increase the risk of insulin resistance, the most common metabolic dysregulation related to obesity. We investigated the association of ENPP1 SNP K121Q (rs1044498) with insulin resistance and ADIPOQ SNP + 267G > T (rs1501299) with circulating adiponectin levels in a case–control study involving 55 obese and 55 lean Javanese people residing in Yogyakarta, Indonesia. Allele frequency was determined by a chi squared test or Fisher’s exact test with an expected value less than 0.05. Odds ratios and 95% confidence intervals were estimated by regression logistic analysis. The presence of the Q121 allele of ENPP1 resulted in significantly higher fasting glucose, fasting insulin levels, and HOMA-IR, as compared to homozygous K121 carriers. The risk of insulin resistance was elevated in obese individuals carrying Q121 instead of homozygous K121. Adiponectin level was significantly lower in the obese group as compared to the lean group. Obese individuals carrying homozygous protective alleles (TT) of ADIPOQ tended to have lower adiponectin levels as compared to GT and GG carriers, however, we did not find statistically significant effects of the +276G > T SNP of the ADIPOQ gene on the plasma adiponectin levels or on the development of obesity.
... It has been shown that, the insulin receptor substrates and phosphatidylinositol 3-kinase (PI3K) are two major mediators regulating insulin dependent glucose transport, however, there may be other pathways involved in glucose uptake (11,12). Additionally, there are evidences that show regulatory genes of the proximal insulin signaling pathway may contribute to insulin resistance and could be potential candidates in pathogenesis of type 2 diabetes (13). Phosphorylated IRSs (insulin receptor substrate proteins) act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 domains, including the p85 subunit of phosphatidylinositol (PI) 3-kinase (7). ...
Type 2 diabetes mellitus (T2DM) is a multi-factorial disease in which influenced by several genetic and environmental factors. Insulin receptor substrate 2 (IRS 2) is the main mediator of insulin in the liver which controls insulin sensitivity. Gly1057Asp polymorphism is one of the candidates to increase risk of T2DM. The present study is an attempt to study the relationship of Gly1057Asp polymorphism of IRS-2 and T2DM by a meta-analysis. A systemic search was conducted in English and Persian databases such as Scopus, PubMed, Google Scholar, SID, and other academic databases for studies that have investigated the relationship of Gly1057Asp polymorphism of IRS-2 and T2DM. This association was determined using odds ratios (ORs) with a confidence interval of 95% (CIs). Heterogeneity of the studies was examined by I2 index. Funnel plots and Egger tests were used to determine bias or publication bias. The collected data was analyzed in STATA through meta-analysis. Nine articles were selected as eligible for further analysis, which represented 3,196 patients with T2DM and 3409 controls subjects without T2DM. The present meta-analysis showed a significant relationship between GA genotype of Gly1057Asp polymorphism and T2DM (OR=0.88; 95% confidence interval, 0.79-0.98), whereas no significant relationship between GG and AA genotype with T2DM was seen; OR for GG and AA genotypes were 1.10 (95% CI, 0.99 -1.22) and 1.13 (95% CI, 0.95- 1.33), respectively. The results of our study show that genotype GA of Gly1057Asp polymorphism of IRS-2 gene plays a protective role and may decrease the risk of T2DM, whereas GG and AA genotypes are considered as a risk factor and related to development of T2DM to some extents.
... The PC-1 K121Q polymorphism is a functional missense alteration (Sortica et al., 2015) in which the 121Q variant binds insulin receptors more firmly than the 121K variant (Costanzo et al., 2001). Previous studies have documented an association of this polymorphism with insulin resistance, T2DM, and metabolic syndrome (Abate et al., 2003;Bhatti et al., 2010;Daoming, Chaoren, Xijun, & Junjun, 2006;Grarup et al., 2006;Marchenko et al., 2018;Vasudevan, Ismail, Ali, & Mansor, 2009). On the other hand, some other studies did not document the genetic association of PC-1 K121Q polymorphism with F I G U R E 1 Genotype of PC-1 alleles on agarose gel. ...
Background: Insulin resistance (IR), known to reduce the response to insulin action,
develops with obesity leading to type 2 diabetes mellitus (T2DM). The PC‐1 gene
has been associated with dyslipidemia, polycystic ovarian disease and T2DM in different
regions of the world. The objective of the present study was to investigate the
genetic association of PC‐1 rs1044498 polymorphism with insulin resistance in type
2 diabetes in the Punjabi population of Pakistan.
Methods: This study was carried out on 161 healthy controls and 161 patients of
T2DM with insulin resistance. Whole blood was collected for DNA extraction and
molecular studies. PCR‐RFLP with AvaII was performed to determine the genotype
in cases and controls. Chi‐square and Hardy Weinberg analyses were carried out.
Statistical analysis was performed by SPSS software.
Results: The demographic data of cases and controls showed significant differences
for different parameters like glucose, insulin, Homeostatic model assessment‐insulin
resistance (HOMA‐IR) and lipid profiles (p < 0.000). Different statistical models
revealed that all the dominant models were found associated in between alleles for
disease risk (p < 0.001) while no association of PC‐1 rs1044498 (K121Q) polymorphism
was found with insulin‐resistant parameters in T2DM cases.
Conclusion: Overall, the results indicate that the K121Q polymorphism was not
found associated with insulin resistance in type 2 diabetes in a Pakistani Punjabi
population. This is the first‐ever report about the genotype of PC‐1 gene in this
population.
KEYWORDS
genetic association, insulin resistance, Pakistan, PC‐1 gene, type 2 diabetes mellitus
... Contrariwise, Morandi et al. stated that the Q121 variant allele of ENPP1 K121Q (rs1044498) SNP presents a protective role for obesity in a study performed on 453 Italian children 33 . Other authors also underlined the relationship between the Q allele of ENPP1 K121Q (rs1044498) SNP and type 2 DM or obesity 31,34 . In contradiction to the afore-mentioned studies, we found no correlations between ENPP1 rs1044498 variant genotype and GWG status. ...
The aims of this study were to establish the role of MC4Rrs17782313 and ENPP1rs1044498 gene polymorphisms on pre-pregnancy BMI and the newborn’s status. We performed a cross-sectional study on 185 mothers and their offspring. The groups were divided into: control group- underweight or normal mothers with BMIinitial < 25 kg/m2 (n1 = 134) and study group-overweight/obese mothers with BMIinitial ≥ 25 kg/m2 (n2 = 51). All subjects underwent demographic, anthropometric, paraclinical, bioimpedance and genetic parameters. We found association between initial BMI and gestational weight gain (GWG), and a higher frequency of excessive GWG in overweight/obese women (p = 0.037). Higher values of anthropometric and bioimpedance parameters were observed in overweight/obese versus underweight/normal women. The MC4R rs17782313 and ENPP1 rs1044498 variant genotypes had an increased risk of pre-pregnancy overweight (OR = 1.41; 95% CI:[0.72; 2.78]; OR = 1.34; 95% CI:[0.65; 2.75]). The newborns from mothers with excessive GWG had a higher birth weight (BW) (p = 0.001). Higher MUAC values were noticed in newborns with MC4R rs17782313 wild-type genotype. Also, BW was correlated with GWG status smoking in pregnancy, gestational age and neonatal ENPP1rs1044498 variant genotype (p = 0.026). Our study pointed out the role of MC4R rs17782313 and ENPP1 rs1044498 genotypes in obesity determinisms in mothers and their newborns in correlation with BMI, MUAC, TST and bioimpedance parameters.
... The PC-1 K121Q polymorphism is a functional missense alteration (Sortica et al., 2015) in which the 121Q variant binds insulin receptors more firmly than the 121K variant (Costanzo et al., 2001). Previous studies have documented an association of this polymorphism with insulin resistance, T2DM, and metabolic syndrome (Abate et al., 2003;Bhatti et al., 2010;Daoming, Chaoren, Xijun, & Junjun, 2006;Grarup et al., 2006;Marchenko et al., 2018;Vasudevan, Ismail, Ali, & Mansor, 2009). On the other hand, some other studies did not document the genetic association of PC-1 K121Q polymorphism with F I G U R E 1 Genotype of PC-1 alleles on agarose gel. ...
Abstract
Background: Insulin resistance (IR), known to reduce the response to insulin action,
develops with obesity leading to type 2 diabetes mellitus (T2DM). The PC‐1 gene
has been associated with dyslipidemia, polycystic ovarian disease and T2DM in different
regions of the world. The objective of the present study was to investigate the
genetic association of PC‐1 rs1044498 polymorphism with insulin resistance in type
2 diabetes in the Punjabi population of Pakistan.
Methods: This study was carried out on 161 healthy controls and 161 patients of
T2DM with insulin resistance. Whole blood was collected for DNA extraction and
molecular studies. PCR‐RFLP with AvaII was performed to determine the genotype
in cases and controls. Chi‐square and Hardy Weinberg analyses were carried out.
Statistical analysis was performed by SPSS software.
Results: The demographic data of cases and controls showed significant differences
for different parameters like glucose, insulin, Homeostatic model assessment‐insulin
resistance (HOMA‐IR) and lipid profiles (p < 0.000). Different statistical models
revealed that all the dominant models were found associated in between alleles for
disease risk (p < 0.001) while no association of PC‐1 rs1044498 (K121Q) polymorphism
was found with insulin‐resistant parameters in T2DM cases.
Conclusion: Overall, the results indicate that the K121Q polymorphism was not
found associated with insulin resistance in type 2 diabetes in a Pakistani Punjabi
population. This is the first‐ever report about the genotype of PC‐1 gene in this
population.
... PC-1 gene polymorphism was associated with Type 2 Diabetes Mellitus in subjects with obesity in the population of Poland, India, and Denmark [16,23]. Differences of the result on PC-1 gene polymorphism in some populations may be due to the interaction between the ethnic pools of genes with environmental factors that affect the expression of phenotypic differences between populations [24]. ...
Java is one of the islands in Indonesia with a large number of overweight and obese population. Obesity is caused by higher energy food intake that is more than needed and is influenced by environment and genetics. This study examined the relationship between polymorphism of K121Q prohormone convertase-1 (PC-1) and Pro-opiomelanocortin (POMC) (C8246T) genes in correlated with leptin level in obese people compared with the control of Javanese ethnic. Subjects consisted of 112 healthy people, involving 56 obese and 56 controls. Determinations of PC-1 and POMC genotypes were done by a polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Determinations of leptin and insulin levels were done with Elisa, and blood sugar levels by GOD-PAP method, with significance set, if p > 0.05. The result was higher and significantly different in blood pressure and leptin level in the obese group compared to the control group. There were no significant differences in POMC and PC-1 genotypes between obese and control groups. Carriers of CC and TC genotypes in the POMC gene had higher leptin levels and were statistically significantly different than the control group. Carriers of GG genotype in PC-1 gene had higher leptin levels in obese group compared to the control group. Polymorphism of POMC (C8246T) and K121Q PC-1 genes can be correlated with leptin level in obese groups of sample Javanese population in Indonesia. Further research is needed to confirm the results of this study and to develop a more comprehensive model of genetic polymorphism related to leptin levels and obesity in ethnic genotypes of Asia.
... The GCKR P446L variant, on the other hand, results in the deregulation of hepatic glucose uptake, increased de novo lipogenesis, decreased serum glucose, and reduced insulin resistance [44,122] . Polymorphisms in the ENPP1 and IRS1 genes involved in insulin signaling result in insulin resistance and are associated with fibrosis in NAFLD [99] as well as risk of incident diabetes [123][124] . While NAFLD is often driven by insulin resistance, genetics predisposing to NAFLD largely do not impact insulin resistance directly. ...
Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition, candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance, inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.
... 23 In some other studies has been observed that the expression level of ENPP1 in patients with insulin resistance has been increased and also it is mentioned that regulatory increased ENPP1level in rat liver, induces insulin resistance and glucose tolerance. [24][25][26] In a multicenter clinical study conducted in Italy and America in 2005, it is observed that increased expression of ENPP1 is associated with a higher prevalence of diabetes and myocardial infarction. 27 So, in this research, we excluded patients with type 2 diabetes and it was found that the level of serum ENPP1 is affected by type 2 diabetes and there is a significant negative relationship between the ENPP1 serum levels and the total calcification score of coronary arteries in non-diabetic patients with cardiovascular disease. ...
Purpose: Coronary artery calcification (CAC) is utilized as an important tool for global risk assessment of cardiovascular events in individuals with intermediate risk. Ecto phosphodiesterase/nucleotide phosphohydrolase-1(ENPP1) converts extracellular nucleotides into inorganic pyrophosphate and it is a key regulator of tissue calcification that adjusts calcification in tissues like vascular smooth muscle cells. The main purpose of this clinical study was to find out the correlation between ENPP1 serum concentration and CAC in human for the first time.
Methods: In this study 83 patients (16 diabetic patients and 67 non-diabetic patients) with coronary artery disease who fulfilled inclusion and exclusion criteria, entered the study. For all patients a questionnaire consisting demographic data and traditional cardiovascular risk factors were completed. Computed tomography (CT)-Angiography was carried out to determine coronary artery calcium score and enzyme-linked immunosorbent assay (ELISA) method was used for measuring ENPP1 serum concentrations.
Results: There was a reverse significant correlation between ENPP1 serum concentration and total CAC score and also CAC of right coronary artery (RCA) (P<0.05) in non-diabetic patients.
Conclusion: On the basis of our results, ENPP1 serum concentration may be a suitable biomarker for coronary artery disease at least in non-diabetic patients. However, more studies with higher sample size are necessary for its confirmation.
