Effect of Plasminogen Activator Inhibitor-1 and Tissue Plasminogen Activator Polymorphisms on Susceptibility to Type 2 Diabetes in Malaysian Subjects

Elevated activity of plasminogen activator inhibitor-1 (PAI-1) and decreased tissue plasminogen activator (tPA) activity are considered to be important risk factors for type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). The aim of this study was to investigate the association of the PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms with T2DM in Malaysian subjects. Serum insulin, coronary risk panel, plasma glucose, and PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms were studied in 303 T2DM subjects (227 with MetS and 76 without MetS) and 131 normal subjects without diabetes and MetS. Statistical analysis showed that the dominant and additive models of PAI-1 4G/5G polymorphism showed a weak association with T2DM without MetS (OR = 2.35, P = 0.045; OR = 1.67, P = 0.058). On the other hand, the recessive model of the tPA Alu-repeat I/D polymorphism showed an association with T2DM with MetS (OR = 3.32, P = 0.013) whereas the dominant and additive models of the tPA Alu-repeat I/D polymorphism were not associated with T2DM either with or without MetS

Association of plasminogen activator inhibitor-1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects

<p>Abstract</p> <p>Background</p> <p>Increased plasma plasminogen activator inhibitor-1 (PAI-1) activity and decreased tissue plasminogen activator (tPA) activity could be considered a true component of the metabolic syndrome (MetS) associated with an increased risk of developing cardiovascular diseases (CVD) and fibrinolytic abnormalities. The aim of this study was to investigate the association of tPA and its inhibitor PAI-1 with type 2 diabetes (T2D) and MetS and interrelationship between PAI-1and tPA activities and antigens in Malaysian T2D and normal subjects.</p> <p>Methods</p> <p>The plasma activities and antigens of PAI-1 and tPA and the levels of the tPA/PAI-1 complex as well as serum insulin, parameter of the coronary risk panel and plasma glucose at fasting state were studied in 303 T2D subjects (227 with MetS and 76 without MetS), 131 normal non-diabetic non-metabolic subjects and 101 non-diabetic MetS subjects.</p> <p>Results</p> <p>The PAI-1 activity was higher in subjects with T2D with MetS (P = 9.8 × 10^-19) and non-diabetic subjects with MetS (P = 3.0 × 10^-15), whereas the tPA activity was lower in T2D with MetS (P = 0.003) as compare to normal subjects. Plasma tPA antigen levels were higher in subjects with T2D with MetS (P = 8.9 × 10^-24), T2D without MetS (P = 1.3 × 10^-13) and non-diabetic MetS subjects (P = 0.002). The activity and antigen of PAI-1 in normal subjects were related to insulin resistance (P = 2.2 × 10^-4; 0.007). Additionally, the PAI-1 activity was associated with an increased waist circumference (P = 2.2 × 10^-4) and decreased HDL-c (P = 0.005), whereas the tPA activity was associated with decreased FBG (P = 0.028). The highest correlation was between PAI-1 activity and its antigen (R²= 0.695, P = 1.1 × 10^-36) in diabetic subjects. The tPA activity negatively correlated with its antigen (R²= -0.444, P = 7.7 × 10^-13) in normal subjects and with the PAI-1 activity and antigen (R²= -0.319, P = 9.9 × 10^-12; R2 = -0.228, P = 3.4 × 10^-6) in diabetic subjects.</p> <p>Conclusions</p> <p>PAI-1 and tPA activities and antigens were associated with diabetes and MetS parameters in Malaysian subjects.</p

Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters in Malaysian subjects

The plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat insertion/deletion polymorphisms might be genetic determinations of increased or decreased of their plasma activities. The aim of this study was to investigate the association of plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat I/D polymorphisms with metabolic syndrome parameters in normal Malaysian subjects and to assess the impact of these polymorphisms on their plasma activities and antigens. The genetic polymorphisms were genotyped in 130 normal subjects. In addition, the plasma activities and antigens of plasminogen activator inhibitor-1 and tissue plasminogen activator as well as levels of insulin, glucose, and lipid profile at fasting state were investigated. The subjects with homozygous 4G/4G showed association with an increased triglyceride (p = 0.007), body mass index (p = 0.01) and diastolic blood pressure (p = 0.03). In addition, the plasminogen activator inhibitor-1 4G/5G polymorphism modulates plasma plasminogen activator inhibitor-1 activity and antigen and tissue plasminogen activator activity (p = 0.002, 0.014, 0.003) respectively. These results showed that, the plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters, plasminogen activator inhibitor-1 and tissue plasminogen activator activities in Malaysian subjects, and may serve to increase the risk of type 2 diabetes and cardiovascular disease in Malaysian subjects

KCNQ1 Haplotypes Associate with Type 2 Diabetes in Malaysian Chinese Subjects

The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) and haplotypes of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) with type 2 diabetes (T2D) in Malaysian Chinese subjects. The KCNQ1 SNPs rs2237892, rs2283228 and rs2237895 were genotyped in 300 T2D patients and 230 control subjects without diabetes and metabolic syndrome. Two logistic regression models of analysis were applied, the first adjusted for age and gender while the second adjusted for age, gender and body mass index. The additive genetic analysis showed that adjusting for body mass index (BMI) even strengthened association of rs2237892, rs2283228 and rs2237895 with T2D (OR = 2.0, P = 5.1 × 10−5; OR = 1.9, P = 5.2 × 10−5; OR = 1.9, P = 7.8 × 10−5, respectively). The haplotype TCA containing the allele of rs2237892 (T), rs2283228 (C) and rs2237895 (A) was highly protective against T2D (Second model; OR = 0.17, P = 3.7 × 10−11). The KCNQ1 rs2237892 (TT), and the protective haplotype (TCA) were associated with higher beta-cell function (HOMA-B) in normal subjects (P = 0.0002; 0.014, respectively). This study found that KCNQ1 SNPs was associated with T2D susceptibility in Malaysian Chinese subjects. In addition, certain KCNQ1 haplotypes were strongly associated with T2D

Association of DPP4 Gene Polymorphisms with Type 2 Diabetes Mellitus in Malaysian Subjects.

BACKGROUND:Genetic polymorphisms of the Dipeptidyl Peptidase 4 (DPP4) gene may play a role in the etiology of type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association of single nucleotide polymorphisms (SNPs) of the DPP4 gene in Malaysian subjects with T2DM and evaluated whether they had an effect on the serum levels of soluble dipeptidyl peptidase 4 (sDPP-IV). METHOD:Ten DPP4 SNPs were genotyped by TaqMan genotyping assays in 314 subjects with T2DM and 235 controls. Of these, 71 metabolic syndrome (MetS) subjects were excluded from subsequent analysis. The odds ratios (ORs) and their 95% confidence interval (CIs) were calculated using multiple logistic regression for the association between the SNPs of DPP4 and T2DM. In addition, the serum levels of sDPP-IV were investigated to evaluate the association of the SNPs of DPP4 with the sDPP-IV levels. RESULTS:Dominant, recessive, and additive genetic models were employed to test the association of DPP4 polymorphisms with T2DM, after adjusting for age, race, gender and BMI. The rs12617656 was associated with T2DM in Malaysian subjects in the recessive genetic model (OR = 1.98, p = 0.006), dominant model (OR = 1.95, p = 0.008), and additive model (OR = 1.63, p = 0.001). This association was more pronounced among Malaysian Indians, recessive (OR = 3.21, p = 0.019), dominant OR = 3.72, p = 0.003) and additive model (OR = 2.29, p = 0.0009). The additive genetic model showed that DPP4 rs4664443 and rs7633162 polymorphisms were associated with T2DM (OR = 1.53, p = 0.039), and (OR = 1.42, p = 0.020), respectively. In addition, the rs4664443 G>A polymorphism was associated with increased sDPP-IV levels (p = 0.042) in T2DM subjects. CONCLUSIONS:DPP4 polymorphisms were associated with T2DM in Malaysian subjects, and linked to variations in sDPP-IV levels. In addition, these associations were more pronounced among Malaysian Indian subjects

Muniandy S. Effect of plasminogen activator inhibitor-1 and tissue plasminogen activator polymorphisms on susceptibility to type 2 diabetes in Malaysian subjects

Elevated activity of plasminogen activator inhibitor-1 (PAI-1) and decreased tissue plasminogen activator (tPA) activity are considered to be important risk factors for type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). The aim of this study was to investigate the association of the PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms with T2DM in Malaysian subjects. Serum insulin, coronary risk panel, plasma glucose, and PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms were studied in 303 T2DM subjects (227 with MetS and 76 without MetS) and 131 normal subjects without diabetes and MetS. Statistical analysis showed that the dominant and additive models of PAI-1 4G/5G polymorphism showed a weak association with T2DM without MetS (OR = 2.35, P = 0.045; OR = 1.67, P = 0.058). On the other hand, the recessive model of the tPA Alu-repeat I/D polymorphism showed an association with T2DM with MetS (OR = 3.32, P = 0.013) whereas the dominant and additive models of the tPA Alu-repeat I/D polymorphism were not associated with T2DM either with or without MetS. Background Diabetes mellitus is the most common endocrine disorder that affects 246 million people worldwide. The International Diabetes Federation (IDF) predicts that the number of people with diabetes mellitus will increase up to 380 million within twenty years Endothelial dysfunction is an emerging risk factor for type 2 diabetes. Obesity, together with the MetS, has a strong association with high PAI-1 levels Alu-repeat I/D polymorphism was found in intron 8 of the tPA gene Materials and Methods 2 For the control group, the consent forms and brochures were distributed to the civil servant of the main office of Radio and Television Malaysia at Bukit Putra, Angkasapuri, Kuala Lumpur, Malaysia, through the Human Resource Department. In addition, consent forms and brochures were distributed to subjects who came to UMMC for medical checkup. After providing written informed consent, 190 normal subjects were randomly recruited for this study. Application of IDF criteria (for diagnose metabolic syndrome) The Medical Ethics Committee of UMMC approved the study. Fasting venous blood (6 mL) was collected from each subject after signed consent form. The collected blood was immediately taken into three labelled Vacutainer sodium fluoride (for glucose measurement), plain (for insulin and lipid profile), and EDTA tubes (for genetic analysis). Biochemical Analysis. Serum TG, HDL-c, and plasma glucose were measured by an automated analyzer Dimension RxL Max Integrated Chemistry System. Insulin was measured by ADVIA Centaur assay XP Immunoassay System (Siemens Healthcare Diagnostics Inc. Deerfield, IL, USA). All these investigation were done at Division of Laboratory Medicine (LMC) of the UMMC, Kuala Lumpur, Malaysia. Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA2) calculator v2.2 which is available from the Oxford Centre for Diabetes, Endocrinology and Metabolism. Genetic Analysis. Leukocyte genomic DNA was extracted from whole EDTA blood using a commercially Wizard Genomic DNA Purification Kit (Promega Corporation, Madison, WI, USA) according to the manufacturer&apos;s instructions. Genotyping of PAI-1 Polymorphisms. Allele-specific PCR was used to detect the genotypes of PAI-1 4G/5G. Two specific forward allele primers 5G, 5 -GAGTCTGGACACGTGGGGG-3 at 3 end is G, and 4G, 5 -GAGTCTGGACACGTGGGGA-3 at 3 end the 5th G was replaced by A as matching the subsequent sequence, were designed to detect this SNP. An internal control was included with each PCR reaction to ensure that there was PCR amplification. Therefore, common forward (upstream of allele-specific primers 5 -TGGTCCCGTTCAGCCACCA-3 ) and reverse primers (downstream of allele-specific primers 5 -ATGCAGCCAGCCACGTGAT-3 ) were used as PCR amplification controls with each PCR reaction. The reverse primer also is a reverse primer for the two allele-specific primers. Amplification reactions of PAI-1 were performed in two separated PCR reactions using 20 µL volume of PCR contained 50 ng of genomic DNA, 5 pmol of allelespecific primer 5G or 4G, 1.2 pmol of forward primer, 5 pmol of reverse primer, 1.5 mM MgCl2, 1X PCR buffer, 1X QSolution, 100 µM dNTPs, and 0.5 unit of HotStarTaq Plus DNA Polymerase (Qiagen, Valencia, CA, USA). DNA was denaturated at 94 • C for 5 min, followed by 25 cycles of denaturation at 94 • C for 1 min, annealing at 63 • C for 45 sec, and extension at 70 • C for 75 sec, with a final extension step for 5 min at 72 • C. The PCR products were run by electrophoresis in a 7% polyacrylamide gel (PAG) and stained with ethidium bromide (EtBr). Band was visualized by the gel document system (Infinity 3026, Vilber Lourmat, Marne-la-Vallée, France). Genotyping of tPA Polymorphism. An I/D polymorphism resulting from the presence or absence of Alurepeat in intron 8 of the tPA gene was assessed by PCR using the following primers • C for 5 min before being subjected to 30 cycles consisting of 1 min at 94 • C (denaturation), 1 min at 60 • C (annealing), and 75 sec at 71 • C (extension) in a thermal cycler followed by final extension at 72 • C for 10 min. 9 µL of each product were electrophoresed on a 1% agarose gel, then stained by EtBr and visualized by the gel document system. To validate the obtained results, samples of PCR products (64 of PAI-1 and 46 of tPA) were sent to Bioneer Corporation (Daejeon, Republic of Korea) for sequencing. The sequencing results were in a good agreement with the PCR results. No errors in allele-specific PCR were detected. Statistical Analysis. Calculations to determine whether observed genotype frequencies are consistent with the Hardy-Weinberg equilibrium (HW) that was done by the Journal of Biomedicine and Biotechnology 3 The result presented as mean ± standard deviation. MetS: metabolic syndrome. T: total. In the additive model, genotype of homozygote for the nonrisk allele 5G/5G (0/0), heterozygote 4G/5G (1/0), and homozygote for the risk allele 4G/4G (1/1) were coded as 0, 1, and 2, respectively. The recessive model was defined as 4G/4G versus (4G/5G + 5G/5G), dominant model as (4G/4G + 4G/5G) versus 5G/5G, and additive model as 4G/4G versus 4G/5G versus 5G/5G. The results presented odds ratio, 95% CI, and P value adjusted for age, gender, race, family history of diabetes, and BMI as covariates which evaluated by hierarchical logistic regression. MetS: metabolic syndrome. method of Court (2005Court ( , 2008. All other statistical analyses were done using Social Package of Statistical Science (SPSS) 11.5 (LEAD Technologies, Inc., USA). The missing data were listwise deleted-when any of the variables were missing, the entire observation was omitted from the analysis. The associations of the PAI-1 and tPA polymorphisms, recessive, dominant, and additive models with T2DM with or without MetS and total T2DM were evaluated by hierarchical logistic regression controlled for age, gender, race, history of diabetes, and BMI as covariates. The difference between means was considered significant when P value &lt;0.05. Results The demographic and biochemical parameters of the subjects are shown in The frequency of the minor allele (4G) of PAI-1 (0.47) was lower than that of the 5G allele (0.53), whereas the frequency of tPA allele insertion (0.48) was lower than that of the allele deletion (0.52). The results showed that the dominant and additive models of PAI-1 4G/5G polymorphism showed a weak association with T2DM without MetS (OR = 2.35, P = 0.045; OR = 1.67, P = 0.058), with no association for T2DM with MetS and total T2DM. Further, the recessive model showed no association of PAI-1 4G/5G genotype with T2DM with or without MetS Discussion The association of the PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms with T2DM with or without MetS as well as with total T2DM was studied in Malaysian subjects. In this study, there were no differences in the frequencies of both polymorphisms PAI-1 4G/5G and tPA Alu-repeat I/D between T2DM and normal subjects. The analysis of genetic models of PAI-1 4G/5G polymorphism (dominant and additive) showed a weak association of polymorphism with T2DM in Malaysian subjects. This weak association may be due to small sample size, particularly in the control group, and nonmatched gender. On the other hand, the recessive model of PAI-1 4G/5G polymorphism showed no association with T2DM in Malaysian subjects. Previous studies had shown significant association with T2DM among the Chinese Genetic data in this study also showed that no differences existed in the allelic frequencies of the insertion and deletion alleles between T2DM with or without MetS as well as total T2DM and normal groups. On the other hand, the recessive model, of the tPA Alu-repeat I/D polymorphism showed a risk factor for T2DM. However, there is limited data on the association of tPA Alu-repeat I/D polymorphism with diseases, while there are no available data on its association with T2DM. Further, its association with other diseases such as myocardial infarction Conclusion The dominant model of PAI-1 4G/5G polymorphism showed a weak association with T2DM without MetS. On the other hand, the recessive model of tPA Alu repeat I/D polymorphism showed a risk factor for T2DM with MetS in Malaysian subjects. Journal of Biomedicine and Biotechnology

Serum Levels of Soluble CD26/Dipeptidyl Peptidase-IV in Type 2 Diabetes Mellitus and Its Association with Metabolic Syndrome and Therapy with Antidiabetic Agents in Malaysian Subjects.

A soluble form of CD26/dipeptidyl peptidase-IV (sCD26/DPP-IV) induces DPP-IV enzymatic activity that degrades incretin. We investigated fasting serum levels of sCD26/DPP-IV and active glucagon-like peptide-1 (GLP-1) in Malaysian patients with type 2 diabetes mellitus (T2DM) with and without metabolic syndrome (MetS), as well as the associations between sCD26/DPP-IV levels, MetS, and antidiabetic therapy.We assessed sCD26/DPP-IV levels, active GLP-1 levels, body mass index (BMI), glucose, insulin, A1c, glucose homeostasis indices, and lipid profiles in 549 Malaysian subjects (including 257 T2DM patients with MetS, 57 T2DM patients without MetS, 71 non-diabetics with MetS, and 164 control subjects without diabetes or metabolic syndrome).Fasting serum levels of sCD26/DPP-IV were significantly higher in T2DM patients with and without MetS than in normal subjects. Likewise, sCD26/DPP-IV levels were significantly higher in patients with T2DM and MetS than in non-diabetic patients with MetS. However, active GLP-1 levels were significantly lower in T2DM patients both with and without MetS than in normal subjects. In T2DM subjects, sCD26/DPP-IV levels were associated with significantly higher A1c levels, but were significantly lower in patients using monotherapy with metformin. In addition, no significant differences in sCD26/DPP-IV levels were found between diabetic subjects with and without MetS. Furthermore, sCD26/DPP-IV levels were negatively correlated with active GLP-1 levels in T2DM patients both with and without MetS. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-cholesterol (LDL-c) levels.Serum sCD26/DPP-IV levels increased in T2DM subjects with and without MetS. Active GLP-1 levels decreased in T2DM patients both with and without MetS. In addition, sCD26/DPP-IV levels were associated with Alc levels and negatively correlated with active GLP-1 levels. Moreover, metformin monotherapy was associated with reduced sCD26/DPP-IV levels. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-c

IGF2BP2 alternative variants associated with glutamic acid decarboxylase antibodies negative diabetes in Malaysian subjects.

BACKGROUND: The association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) common variants (rs4402960 and rs1470579) with type 2 diabetes (T2D) has been performed in different populations. The aim of this study was to evaluate the association of alternative variants of IGF2BP2; rs6777038, rs16860234 and rs7651090 with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian Subjects. METHODS/PRINCIPAL FINDINGS: IGF2BP2; rs6777038, rs16860234 and rs7651090 single nucleotide polymorphisms (SNPs) were genotyped in 1107 GADA negative diabetic patients and 620 control subjects of Asian from Malaysia. The additive genetic model adjusted for age, race, gender and BMI showed that alternative variants; rs6777038, rs16860234 and rs7651090 of IGF2BP2 associated with GADA negative diabetes (OR = 1.21; 1.36; 1.35, P = 0.03; 0.0004; 0.0002, respectively). In addition, the CCG haplotype and diplotype CCG-TCG increased the risk of diabetes (OR = 1.51, P = 0.01; OR = 2.36, P = 0.009, respectively). CONCLUSIONS/SIGNIFICANCE: IGF2BP2 alternative variants were associated with GADA negative diabetes. The IGF2BP2 haplotypes and diplotypes increased the risk of diabetes in Malaysian subject