Related Metabolic Traits Research Articles

Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ∼470,000 CpG sites was assayed in CD4+ T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 × 10−7 was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 × 10−7) and HOMA-IR (P = 1.60 × 10−9). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 × 10−7 and P = 3.36 × 10−6, respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 × 10−3 and P = 3.35 × 10−2, respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker.

Studies of association of AGPAT6variants with type 2 diabetes and related metabolic phenotypes in 12,068 Danes

BackgroundType 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population.MethodsEleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case–control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study.ResultsNone of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case–control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity.ConclusionsCommon and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied.

Diabetes Subphenotypes and Metabolomics: The Key to Discovering Laboratory Markers for Personalized Medicine?

For decades, glucose, hemoglobin A1c, insulin, and C peptide have been the laboratory tests of choice to detect and monitor diabetes (1). However, these tests do not identify individuals at risk for developing type 2 diabetes (T2Dm)4 (so-called prediabetic individuals and the subphenotypes therein), which would be a prerequisite for individualized prevention. Nor are these parameters suitable to identify T2Dm subphenotypes, a prerequisite for individualized therapeutic interventions. The oral glucose tolerance test (oGTT) is still the only means for the early and reliable identification of people in the prediabetic phase with impaired glucose tolerance (IGT). This procedure, however, is very time-consuming and expensive and is unsuitable as a screening method in a doctor′s office. Hence, there is an urgent need for innovative laboratory tests to simplify the early detection of alterations in glucose metabolism. The search for diabetic risk genes was the first and most intensively pursued approach for individualized diabetes prevention and treatment. Over the last 20 years cohorts of tens of thousands of people have been analyzed, and more than 70 susceptibility loci associated with T2Dm and related metabolic traits have been identified (2). But despite extensive replication, no susceptibility loci or combinations of loci have proven suitable for diagnostic purposes. Why did the genomic studies fail? One reason might be that T2Dm is a polygenetic disease, but there is another more important reason. The large diabetes cohorts investigated in these studies were very heterogeneous, consisting of poorly characterized individuals who were usually selected because they had an increase in blood glucose. Subsequently it has become clear that many different subphenotypes already exist in the prediabetic phase (3, 4). Metabolomics represents a new potential approach to move the diagnosis of diabetes beyond the application of the classical diabetic laboratory tests. This strategy means …

Abstract 358: Association of Adiponectin-with Cardio-metabolic Traits

Background and Objectives Current evidence on the association of adiponectin with fatal or non-fatal cardiovascular (CVD) outcomes is inconsistent. In addition association between adiponectin and related metabolic traits has not been systematically evaluated. Design and Methods A systematic search was performed using MEDLINE and Web of Science databases. Effect estimates and standard errors of associations of adiponectin with metabolic traits including (adiposity, glucose, insulin and cholesterol) and cardiovascular outcomes (coronary heart disease and stroke) were extracted from relevant prospective studies. The effect estimates and standardized correlation coefficients were pooled together using random effects meta-analysis. Results A total of 18 studies with 32,116 participants and 7,433 cardiovascular events reported on associations for adiponectin. Moderately strong and inverse associations were observed for adiponectin and measures of adiposity, body mass index, r=-0.13 [95% CI -0.29 to -0.02], waist to hip ratio, (r=-0.25 [95% CI -0.31 to -0.21] and waist circumference, r=-0.23 [95% CI -0.29 to -0.16]. Similarly inverse associations were seen with glucose, r=-0.19 [95% CI -0.22 to -0.17], insulin, r=-0.27 [95% CI -0.38 to -0.15] and triglycerides r=-0.31[95% CI -0.36, -0.26] while a positive correlation was observed with HDL-c, r=0.35[95% CI 0.30-0.41]. A pooled adjusted RR[95% CI] of 0.99 (95% CI: 0.86 to 1.14) with CVD for individuals in the top versus bottom third of baseline levels of adiponectin was seen. There was evidence of moderate heterogeneity between the findings of contributing studies (I2 =66%) with little difference explained by several study-level characteristics. Similarly modest associations were observed for both coronary heart disease (CHD), RR[95% CI] 0.89 (0.74 to 1.08) and stroke RR[95% CI] 1.01 (0.83 to 1.22). Conclusion Results of this systematic analysis give further evidence to the role of adiponectin with metabolic traits. However observational evidence from prospective studies indicates modest association with CHD and stroke outcomes that needs further investigation.

RETRACTED ARTICLE: Common variation in PPARGC1A/B and progression to diabetes or change in metabolic traits following preventive interventions: the Diabetes Prevention Program

AIMS/HYPOTHESIS: PPARGC1A and PPARGC1B encode transcriptional coactivators that regulate numerous type 2 diabetes-related metabolic processes. Common genetic variation across PPARGC1A/B was characterised by genotyping tagging variants. We then tested associations of these variants with diabetes incidence or change in quantifiable metabolic traits directly or via interactions (with metformin treatment or intensive lifestyle modification) in the Diabetes Prevention Program (DPP), a randomised controlled trial in persons at high risk of type 2 diabetes. METHODS: We used Tagger software to select 75 PPARGC1A and 94 PPARGC1B tag single nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for association with diabetes incidence using Cox proportional hazards regression models, and a range of relevant metabolic quantifiable traits, using generalised linear models. RESULTS: Eight PPARGC1A variants were nominally (p < 0.05) associated with diabetes incidence, of which one (rs3736265/Thr612Met) was associated with diabetes in the DPP (HR 1.31, 95% CI 1.05, 1.63 per copy of the 612Met allele) and in the DIAGRAM database (OR 1.11, 95% CI 1.01, 1.21). Consistent with earlier reports, the Gly482Ser (rs8192678) variant showed nominally significant effects on 1 year accumulation of adiposity and worsening insulin resistance (both p < 0.05). A third PPARGC1A variant (rs2970852) modified the effects of metformin on triacylglycerol levels (p interaction = 0.04; p = 0.0001 for association of SNP with triacylglycerol concentrations in metformin-treated participants). A number of other PPARGC1A/B variants were nominally directly associated with diabetes incidence or modified treatment effects on diabetes incidence. CONCLUSIONS/INTERPRETATION: These findings provide some novel and confirmatory insights into the roles of PPARGC1A/B variation in type 2 diabetes and related metabolic traits. TRIAL REGISTRATION: ClinicalTrials.gov NCT00004992. (Less)

A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

BackgroundGenome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.ResultsDisrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.ConclusionCandidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.

Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4Rgenes to obesity in Mexican children

BackgroundRecent genome wide association studies (GWAS) and previous positional linkage studies have identified more than 50 single nucleotide polymorphisms (SNPs) associated with obesity, mostly in Europeans. We aimed to assess the contribution of some of these SNPs to obesity risk and to the variation of related metabolic traits, in Mexican children.MethodsThe association of six European obesity-related SNPs in or near FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes with risk of obesity was tested in 1,463 school-aged Mexican children (Ncases = 514; Ncontrols = 949). We also assessed effects of these SNPs on the variation of body mass index (BMI), fasting serum insulin levels, fasting plasma glucose levels, total cholesterol and triglyceride levels, in a subset of 1,171 nonobese Mexican children.ResultsWe found a significant effect of GNPDA2 rs10938397 on risk of obesity (odds ratio [OR] = 1.30; P = 1.34 × 10-3). Furthermore, we found nominal associations between obesity risk or BMI variation and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Importantly, the at-risk alleles of both MC4R rs17782313 and NPC1 rs1805081 showed significant effect on increased fasting glucose levels (β = 0.36 mmol/L; P = 1.47 × 10-3) and decreased fasting serum insulin levels (β = −0.10 μU/mL; P = 1.21 × 10-3), respectively.ConclusionOur present results suggest that some obesity-associated SNPs previously reported in Europeans also associate with risk of obesity, or metabolic quantitative traits, in Mexican children. Importantly, we found new associations between MC4R and fasting glucose levels, and between NPC1 and fasting insulin levels.

Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits

Genome-wide association studies have identified genetic variants associated with increased risk of type 2 diabetes. The aim of this review is to highlight some of the insights into the mechanism underlying type 2 diabetes provided by genetic association studies.

Polymorphisms of INSIG2, MC4R, and LEP Are Associated With Obesity- and Metabolic-Related Traits in Schizophrenic Patients

Polymorphisms of INSIG2, MC4R, and LEP Are Associated With Obesity- and Metabolic-Related Traits in Schizophrenic Patients

The frequent UCP2 −866G&gt;A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes

Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in β-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus. To determine the influence of a functional UCP2 promoter polymorphism (-866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes. We genotyped UCP2 rs659366 in a total of 17 636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations. We found no consistent associations between the UCP2 -866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12 984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826-0.968) P=0.00562, and AA vs GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15 107 individuals showed no association. The -866G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects (n=377) was decreased in carriers of the GG genotype (P=0.05). The UCP2 -866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.

Association of leptin receptor gene polymorphisms and essential hypertension in a Chinese population.

The leptin receptor (LEPR) is an important regulator of leptin activity and resistance. Several single nucleotide polymorphisms (SNP) of LEPR have been linked to diseases accompanying obesity and/or obesity-related diseases in different populations. However, the results from published studies remain inconsistent rather than conclusive. To investigate whether LEPR SNP are associated with essential hypertension and related metabolic traits in Chinese subjects. A total of 544 Chinese patients with hypertension and 357 non-hypertensive subjects were screened. The genotypes of LEPR polymorphisms were determined by PCR-restriction fragment length polymorphism methods. Demographic and biochemical characteristics including waist circumference, waist-to-hip ratio, body mass index (BMI), lipids profiles, glucose metabolism, and leptin levels were obtained for analysis. This case-control study showed associations between the frequencies of AA genotype and A allele of Gln223Arg and hypertension (p=0.029, p=0.002, respectively). Furthermore, the Gln223Arg polymorphism was significantly associated with plasma leptin levels (p<0.001), while no correlations between Lys109Arg SNP and hypertension were found. Multivariate logistic regression analysis evidenced that A allele carriers of Gln223Arg (AA+AG) showed higher risks of hypertension than GG carriers after adjustment of age and sex (adjusted odds ratio: 1.549, 95% confidence interval: 1.031- 2.036, p=0.035). BMI, fasting serum insulin, oral glucose tolernace test (OGTT)-2h glucose, serum leptin, as well as LDL-cholesterol (LDL-C) levels were also independent risk factors of hypertension in this population. In addition, significant associations were observed between the Gln223Arg and Lys109Arg SNP and serum total cholesterol, LDL-C, and fasting plasma glucose levels in hypertensive patients. Besides, A allele of Gln223Arg had raised diastolic blood pressure, compared with GG carriers (p=0.001). While variance of Lys109Arg was associated with waist-to-hip ratio, OGTT-2h glucose, and homeostasis model assessment of insulin resistance (p<0.05). LEPR polymorphisms may be a marker for susceptibility to essential hypertension in Chinese subjects, and be involved in the development of several features including dyslipidemia and impaired glucose regulation in hypertension subjects.

Type 2 Diabetes Genetics: Beyond GWAS

The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.

Prevalence of metabolic syndrome and related metabolic traits in an island population of the Adriatic

Background: Metabolic syndrome, a constellation of risk factors associated with cardiovascular disease and Type 2 diabetes, has reached epidemic proportions worldwide. Epidemiological studies in transitional societies will provide insight into the underlying factors that interact in its manifestation.Aims: To estimate the prevalence of metabolic syndrome, provide a comparative analysis of two metabolic syndrome definitions and assess clustering and association of metabolic traits and cardiovascular diseases in an Adriatic island population.Subjects and methods: In a cross-sectional study, data on four anthropometric, blood pressure and 11 biochemical traits were obtained from 1430 adults from the island of Hvar.Results: Prevalence of metabolic syndrome was 25% and 38.5% based on Adult Treatment Panel III and International Diabetes Federation definitions, respectively. Rates of abdominal obesity, elevated blood glucose and hypertension were high. Among the traits not included in the definitions, levels of LDL, total cholesterol and fibrinogen were markedly elevated. The majority of the phenotypes were significantly associated with the syndrome, the strongest being waist circumference.Conclusion: The Croatian islanders are characterized by a high prevalence of metabolic abnormalities. Central obesity is the strongest contributor of the syndrome. With a high prevalence of dyslipidemia and pro-inflammatory factors, the population is at substantial risk for cardiovascular diseases.

Polymorphisms of INSIG2, MC4R, and LEP Are Associated With Obesity- and Metabolic-Related Traits in Schizophrenic Patients

Schizophrenic patients have a high prevalence of metabolic adversities. Previous studies have suggested some candidate genes for obesity- and metabolic-related traits, including the insulin-induced gene (INSIG2), melanocortin 4 receptor gene (MC4R), and leptin and leptin receptor genes (LEP and LEPR). We aimed to investigate the associations between these genes and metabolic disturbances in patients with schizophrenia in Taiwan. Patients with a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were recruited from 36 community psychiatric rehabilitation centers or hospitals in Taipei. A total of 650 subjects were enrolled, and 577 were included in the genetic analyses. The anthropometric (body mass index, waist circumference [WC], and blood pressure) and biochemical measurements (fasting plasma glucose, insulin, triglyceride, high-density lipoprotein cholesterol, and Homeostasis Model of Assessment - Insulin Resistance index [HOMA-IR]) were assessed. Seven loci in the 4 genes were genotyped using standard TaqMan assays. Genetic association analyses were conducted for binary and quantitative measurements of the previously mentioned traits. Obese patients with schizophrenia exhibited more metabolic disturbances than nonobese patients. Our data showed that INSIG2 was significantly associated with fasting plasma glucose (for rs17587100, P < 0.0001), MC4R was associated with WC (for rs2229616, P = 0.005), and LEP was associated with body mass index and WC (for rs7799039, P < 0.01). In addition, these loci showed suggestive associations with traits including high-density lipoprotein cholesterol and triglyceride, metabolic syndrome, insulin level, and HOMA-IR index (P = 0.05). In addition to the effect from antipsychotic medications and an unhealthy lifestyle, genetic factors also contribute to the high prevalence of obesity and metabolic disturbances in patients with schizophrenia, especially genes involved in metabolic-related pathways.

Early growth and coronary heart disease and type 2 diabetes: findings from the Helsinki Birth Cohort Study (HBCS)

A slow rate of intrauterine growth is a major risk factor for several common noncommunicable diseases, which include the following: coronary heart disease (CHD), hypertension, and type 2 diabetes. Likewise, growth patterns in infancy and childhood have been identified as important factors linked to the pathogenesis of these disorders. In this overview, patterns of growth associated with CHD, type 2 diabetes, and related metabolic traits in adult life are presented on the basis of findings from the Helsinki Birth Cohort Study (HBCS) 1934-1944. Later risk of CHD was associated with small body size at birth and during infancy, followed by an increase in body size later in childhood. This pattern of growth has been associated with dyslipidemia in later life, which offers an explanation for the observed findings. Type 2 diabetes and CHD share several risk factors. The early growth of persons who later develop type 2 diabetes includes a small body size at birth as well as a small body size during infancy. An early age at adiposity rebound was associated with a markedly increased risk of type 2 diabetes in adulthood. The patterns of growth associated with type 2 diabetes are also associated with alterations in body composition, which predisposes to insulin resistance and the metabolic syndrome. The presented findings suggest that to be able to understand the pathogenesis of several noncommunicable diseases, the diseases need to be studied from a life-course perspective, and prenatal and childhood growth as well as adult characteristics need to be taken into account.

Serotonin Receptor 2A −1438G/A Promoter Polymorphism in Relation to Obesity and Response to Sibutramine

Serotonin has been related to appetite and body weight control. The aim of this study was to investigate a possible association of the -1438 /A promoter polymorphism of the serotonin 2A receptor (5HT2AR) gene with obesity-related variables and response to sibutramine. We examined the potential impact of this polymorphism on obesity and related metabolic traits in a cohort of 234 overweight/obese and 103 lean Greek subjects. Additionally, we examined whether the 5HT2AR 1438A/G polymorphism influences weight reduction and change in body composition among 106 out of these subjects, who were treated with 15 g sibutramine. Genotyping was carried out by polymerase chain reaction and restriction enzyme analysis. Body mass index, fat mass, and waist circumference were not significantly different across the 5HT2AR 1438A/G genotype groups in overweight/obese women. Polymorphic G allele was associated with higher triglyceride and insulin levels but not with other biochemical and metabolic parameters. Distribution of genotypes and alleles was not different between responders and nonresponders (weight loss >5 or <5 g). Based on these results, it seems unlikely that the 5HT2AR 1438 /A polymorphism has a major impact on obesity and related traits or the response to sibutramine in Greek overweight/obese subjects.

Estrogen receptor alpha gene polymorphisms are associated with type 2 diabetes and fasting glucose in male subjects

The PvuII and XbaI polymorphisms of the estrogen receptor α (ER1) gene have been variably associated with type 2 diabetes (T2D) in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that the ER1 variants might be associated with T2D and related metabolic traits in this population. The PvuII and XbaI genotypes were determined by PCR-RFLP in 377 normoglycemic controls and 155 T2D patients. Bonferroni correction was applied for the correction of multiple testing. No significant association was found between the allele and genotype frequencies of PvuII and XbaI variants with T2D in females. In a dominant model (PP vs. Pp+pp), the frequency of the Pp+pp genotype was higher in normoglycemic subjects compared to T2D patients [85.5% vs. 66.7%, OR 0.22 (0.08-0.55), P=0.001]. Four possible haplotypes were observed in the population, whereas haplotype TA had a higher frequency in male T2D subjects than the controls. Furthermore, non-diabetic male subjects carrying the genotype of PP had a higher fasting glucose levels than the individuals with the genotype of Pp+pp (P=0.013). Multivariate logistic regression analysis showed that PvuII polymorphism was the independent determinants of T2D in males [OR 4.37 (1.61-11.86), P=0.004]. No association was found between the XbaI polymorphism and diabetes in male group. Our results suggest that the ER1 polymorphisms might associate with T2D and fasting glucose among Iranian male subjects.

Role of Genetic Variation in the Human Sodium–Glucose Cotransporter 2 Gene ( SGLT2 ) in Glucose Homeostasis

Mutations in the sodium-glucose cotransporter 2 (SGLT2), as well as treatment with SGLT2 inhibitors result in reduced fasting glucose levels, HbA(1c) and BMI. We therefore investigated the effects of common genetic variation in SGLT2 on human Type 2 diabetes and related traits. Four HapMap tagging SNPs covering the common genetic variation in SGLT2 (r² > 0.8 and minor allele frequency > 0.01) were genotyped for subsequent association studies on BMI, Type 2 diabetes and related metabolic traits in 1013 Sorbs (Germany). An independent cohort from Berlin (n = 2042) was taken for replication. The rs9934336 G-allele was nominally associated with increased 30-min plasma glucose, 120-min insulin concentrations and AUC120min(glucose) during oral glucose tolerance test in 907 nondiabetic Sorbs (p < 0.05). In the combined analysis including the Sorbs and the Berlin cohort, rs9934336 was nominally associated with 120-min insulin concentrations (adjusted p < 0.05) in nondiabetic subjects (n = 2590). Our data suggest a role of SGLT2 genetic variation in the regulation of glucose homeostasis and promote pharmacogenomic studies to clarify the efficacy of antidiabetic treatment by SGLT2 inhibitors.

Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes

BackgroundTwo meta-analyses of genome-wide association studies (GWAS) have suggested that four variants: rs2605100 in lysophospholipase-like 1 (LYPLAL1), rs10146997 in neuroxin 3 (NRXN3), rs545854 in methionine sulfoxide reductase A (MSRA), and rs987237 in transcription factor activating enhancer-binding protein 2 beta (TFAP2B) associate with measures of central obesity.To elucidate potential underlying phenotypes we aimed to investigate whether these variants associated with: 1) quantitative metabolic traits, 2) anthropometric measures (waist circumference (WC), waist-hip ratio, and BMI), or 3) type 2 diabetes, and central and general overweight and obesity.Methodology/Principal FindingsThe four variants were genotyped in Danish individuals using KASPar®. Quantitative metabolic traits were examined in a population-based sample (n = 6,038) and WC and BMI were furthermore analyzed in a combined study sample (n = 13,507). Case-control studies of diabetes and adiposity included 15,326 individuals. The major G-allele of LYPLAL1 rs2605100 associated with increased fasting serum triglyceride concentrations (per allele effect (β) = 3%(1;5(95%CI)), p additive = 2.7×10−3), an association driven by the male gender (p interaction = 0.02). The same allele associated with increased fasting serum insulin concentrations (β = 3%(1;5), p additive = 2.5×10−3) and increased insulin resistance (HOMA-IR) (β = 4%(1;6), p additive = 1.5×10−3). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (β = 0.55cm (0.20;0.89), p additive = 1.7×10−3, p interaction = 1.0×10−3), but showed no associations with obesity related metabolic traits. The MSRA rs545854 and TFAP2B rs987237 showed nominal associations with central obesity; however, no underlying metabolic phenotypes became obvious, when investigating quantitative metabolic traits. None of the variants influenced the prevalence of type 2 diabetes.Conclusion/SignificanceWe demonstrate that several of the central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B associate with metabolic and anthropometric traits in Danish adults. However, analyses were made without adjusting for multiple testing, and further studies are needed to confirm the putative role of LYPLAL1, NRXN3, MSRA, and TFAP2B in the pathophysiology of obesity.

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.