Daniel Petrovič

Association of Vascular Endothelial Growth Factor Gene Polymorphism with Myocardial Infarction in Patients with Type 2 Diabetes

Background: Many studies have reported increased serum levels of vascular endothelial growth factor (VEGF) in patients with acute coronary syndromes. We searched for the association between either the –634 C/G or the insertion/deletion (I/D) polymorphism of the VEGF gene and myocardial infarction (MI) in subjects with type 2 diabetes. Methods: 143 subjects with type 2 diabetes and MI were compared to 228 diabetic subjects without coronary artery disease (CAD). VEGF serum levels were analyzed in 94 subjects with type 2 diabetes without CAD. Results: A significantly higher frequency of the CC genotype of the –634 C/G VEGF polymorphism was found in the patients with MI compared to the patients without CAD (17.5 vs. 9.2%; p = 0.019), whereas the insertion/deletion VEGF polymorphism failed to yield an association with MI. Significantly higher VEGF serum levels were demonstrated in subjects with the CC genotype compared to those with the other (CG + GG) genotypes (60.4 ± 32.1 vs. 44.1 ± 23.5 ng/l; p < 0.01). Conclusions: The present study demonstrates that the CC genotype of the –634 C/G VEGF gene might be a risk factor for MI in Caucasians with type 2 diabetes of duration of more than 10 years.

Manganese Superoxide Dismutase Gene Polymorphism (V16A) is Associated with Diabetic Retinopathy in Slovene (Caucasians) Type 2 Diabetes Patients

Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy. Two candidate genes that affect the oxidative stress are manganese mitochondrial superoxide dismutase (Mn-SOD) and endothelial nitric oxide synthase (eNOS). The aim of the present study was to examine the role of the V16A polymorphism of the Mn-SOD gene and the 4a/b polymorphism of the eNOS gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes. In this cross sectional case-control study 426 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 283 patients with diabetic retinopathy and the control group of 143 subjects with type 2 diabetes of duration of more than 10 years who had no clinical signs of diabetic retinopathy. A significantly higher frequency of the VV genotype of the V16A polymorphism of the Mn-SOD was found in patients with diabetic retinopathy compared to those without diabetic retinopathy (OR=2.1, 95% CI = 1.2–3.4; p = 0.006), whereas the 4a/b polymorphism of the eNOS gene failed to yield an association with diabetic retinopathy. We may conclude that the VV genotype of the V16A polymorphism of the Mn-SOD gene was associated with diabetic retinopathy in Caucasians with type 2 diabetes, therefore it might be used as a genetic marker of diabetic retinopathy in Caucasians.

Predictive role of circulating endothelial-derived microparticles in cardiovascular diseases

Endothelial-derived microparticles (EMPs) are a novel biological marker of endothelium injury and vasomotion disorders that are involved in pathogenesis of cardiovascular, metabolic, and inflammatory diseases. Circulating levels of EMPs are thought to reflect a balance between cell stimulation, proliferation, apoptosis, and cell death. Increased EMPs may be defined in several cardiovascular diseases, such as stable and unstable coronary artery disease, acute and chronic heart failure, hypertension, arrhythmias, thromboembolism, asymptomatic atherosclerosis as well as renal failure, metabolic disorders (including type two diabetes mellitus, abdominal obesity, metabolic syndrome, insulin resistance) and dyslipidemia. This review highlights the controversial opinions regarding impact of circulating EMPs in major cardiovascular and metabolic diseases and summarizes the perspective implementation of the EMPs in risk stratification models.

Candidate Genes for Proliferative Diabetic Retinopathy

Several candidate genes have been so far implicated in the pathogenesis of proliferative diabetic retinopathy (PDR) in subjects with type 2 diabetes. Since the principal pathogenetic mechanisms for diabetic retinopathy (DR) and PDR are different, the main pathogenetic mechanism in DR is increased vascular permeability, whereas in PDR the crucial pathogenetic mechanisms are fibrosis and neoangiogenesis. Due to that fact, different candidate genes are expected to be involved in the development of either DR or PDR. None of the candidate genes, however, can be fully and solely responsible for the development of PDR and for DR progression into PDR. Epigenetic mechanisms are expected to be involved in the pathogenesis of PDR as well. Gene polymorphisms responsible for PDR and epigenetic mechanisms responsible for PDR are reviewed in this paper.

GSTT1 Null Genotype Is a Risk Factor for Diabetic Retinopathy in Caucasians with Type 2 Diabetes, whereas GSTM1 Null Genotype Might Confer Protection against Retinopathy

Aim: Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy (DR). The aim of the present study was to investigate whether the genetic polymorphisms: polymorphic deletions of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) and Ile105Val of the GSTP1 are associated with DR in Slovenian patients with type 2 diabetes. Methods: In this cross sectional case-control study 604 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 284 patients with DR (cases) and the control group of 320 subjects with type 2 diabetes of more than 10 years’ duration who had no clinical signs of DR. Genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results: In our study, the deletion of the GSTM1 was found less frequent in cases with DR than in the controls (27.5% versus 44.4%; P < 0.001), whereas the deletion of GSTT1 was found significantly more often in cases than in the controls (49.3% versus 29.7%;P < 0.001). We did not find statistically significant differences in the genotype distribution in GSTP1 (Ile105Val) polymorphism between cases and controls (40.5% versus 46.0%). Conclusions: We may conclude that individuals homozygous for the deletion of GSTT1 are at an ≈ 2-fold-greater risk of DR, whereas the GSTM1 deficiency is associated with lower frequency of DR in type 2 diabetics.

Apoptosis of myocytes and proliferation markers as prognostic factors in end-stage dilated cardiomyopathy.

INTRODUCTION The aim of the study was to evaluate the role of apoptosis, proliferation markers, volume density of interstitium, and myofibril volume fraction for the prognosis in patients with end-stage dilated cardiomyopathy (DCM). METHODS Endomyocardial biopsy was performed during open-heart surgery in 56 patients with end-stage DCM. Patients were divided into two groups, one group with shorter survival (24+/-9 months, mean+/-S.D.) and another group with survival of more than 7 years after operation. The TUNEL method was used for the detection of apoptosis, and immunohistochemical methods were used for the evaluation of inhibitor of apoptosis (bcl-2) and proliferation markers (PCNA and Ki-67). RESULTS The increased percentage of apoptotic myocytes, decreased expression of bcl-2, and decreased expression of PCNA and Ki-67 antigen was found in the group with early mortality compared to that with longer survival. Myofibril volume fraction was lower and volume density of interstitium was higher in the group with early mortality compared to that with longer survival. CONCLUSION Apoptosis, bcl-2 expression, and proliferation activity of myocytes, myofibril volume fraction, and volume density of interstitial tissue might be useful in predicting the prognosis (progressive vs. nonprogressive form) of patients with heart failure due to DCM.

Gly482Ser polymorphism of the peroxisome proliferator–activated receptor‐γ coactivator‐1 gene might be a risk factor for diabetic retinopathy in Slovene population (Caucasians) with type 2 diabetes and the Pro12Ala polymorphism of the PPARγ gene is not

The peroxisome proliferator–activated receptor‐gamma (PPARγ) gene has been recently associated with type 2 diabetes, obesity and traits depending on VEGF expression (e.g. retinopathy). The PPARγ gene and its coactivator, the peroxisome proliferator–activated receptor‐gamma coactivator‐1 (PPARGC1) gene, have been implicated to be involved in glucose uptake and altered lipid oxidation. We therefore hypothesized that the Gly482Ser polymorphism of the PPARGC1 gene and Pro12Ala polymorphism of the PPARγ gene might confer susceptibility to diabetic retinopathy in type 2 diabetes. The aim of this study was to investigate the association between the Pro12Ala polymorphism in the PPARγ gene and Gly482Ser polymorphism in the PPARGC1 gene and the development of diabetic retinopathy in the Slovene population (Caucasians) with type 2 diabetes.

A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes

AbstractIron metabolism might be involved in the pathogenesis of type 2 diabetes and in the pathogenesis of diabetic retinopathy. C282Y and H63D mutations in the hemochromatosis (HFE) gene are associated with increased serum iron levels and consequently with hereditary hemochromatosis. In the present study, we searched for a relationship between C282Y and H63D gene mutations and the development of proliferative diabetic retinopathy in Caucasians with type 2 diabetes. For this purpose, 90 subjects with type 2 diabetes with proliferative diabetic retinopathy (PDR) were compared to 133 diabetic subjects without PDR. There was a significantly higher frequency of the C282Y heterozygotes in patients with PDR compared to subjects without it (OR=3.0, 95% CI=1.2–8.0; p=0.02), whereas no association was demonstrated between PDR and H63D genotypes (OR=1.1, 95% CI=0.6–2.2; p=0.7). Logistic regression analysis revealed that the C282Y mutation was a significant independent risk factor for the development of PDR (OR=6.1, 95% CI=1.2–30.5; p=0.027). These data suggest that heterozygosity for C282Y might be a novel risk factor for PDR in Caucasians with type 2 diabetes.

K469E polymorphism of the intracellular adhesion molecule 1 gene is associated with proliferative diabetic retinopathy in Caucasians with type 2 diabetes.

Background:  In proliferative diabetic retinopathy (PDR) increased levels of cytokines, inflammatory cells and angiogenic factors are present. These factors increase the expression of cellular adhesion molecules (CAMs) The objective of this study was to investigate the association between the polymorphisms of the ICAM‐1 gene (K469E, G241A) and the development of PDR among patients with type 2 diabetes in the Slovenian population (Caucasians).

Insertion/Deletion Plasminogen Activator Inhibitor 1 and Insertion/Deletion Angiotensin-Converting Enzyme Gene Polymorphisms in Diabetic Retinopathy in Type 2 Diabetes

In an association study, the relationship between the insertion/deletion (I/D) plasminogen activator inhibitor 1 (PAI-1) gene polymorphism or the I/D angiotensin 1-converting enzyme (ACE) gene polymorphism and the development of diabetic retinopathy in patients with type 2 diabetes was investigated. One hundred and twenty-four subjects with type 2 diabetes and diabetic retinopathy were compared to 80 diabetic subjects without retinopathy with diabetes of a duration of more than 10 years. The PAI-1 gene distribution and ACE gene distribution in patients with diabetic retinopathy (4G4G 31.4%, 4G5G 46.8%, 5G5G 21.8%; DD 26.6%, ID 50.8%, II 22.6%) were not significantly different from those of diabetic subjects without retinopathy (4G4G 31.3%, 4G5G 50%, 5G5G 18.7%; DD 31.3%, ID 40%, II 28.7%). Neither the 4G/5G PAI-1 gene polymorphism nor the I/D ACE gene polymorphism contributed to the genetic susceptibility to diabetic retinopathy, either non-proliferative, proliferative or severe proliferative diabetic retinopathy, i.e. visual acuity of 0.1 or less in the better eye, in a group of Caucasian subjects with type 2 diabetes.