Mojca Globočnik 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.

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.

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).

BglII gene polymorphism of the α2β1 integrin gene is a risk factor for diabetic retinopathy in Caucasians with type 2 diabetes

AbstractPlatelets are thought to be involved in the pathogenesis of diabetic retinopathy. The BglII gene polymorphism of the α2β1 integrin, which is a platelet collagen receptor, has been suggested as a genetic risk factor for diabetic retinopathy in Japanese subjects. The aim of this study was to look for a relationship between the BglII gene polymorphism of the α2β1 integrin gene and the development of diabetic retinopathy in Caucasians with type 2 diabetes. Subjects with type 2 diabetes and diabetic retinopathy (n=163) were compared with diabetic subjects without diabetic retinopathy (n=95). A significantly higher frequency of the BglII (+/+) genotype of the gene polymorphism of the α2β1 integrin gene was found in patients with diabetic retinopathy compared with patients without diabetic retinopathy (19.6% vs 7.4%; P=0.008). The present study demonstrates that the BglII (+/+) genotype of the gene polymorphism of the α2β1 integrin gene is an independent risk factor (odds ratio: 2.4, 95% confidence interval 1.0-6.0; P<0.05) for diabetic retinopathy in Caucasians with type 2 diabetes.

Sex Difference in the Effect of ACE-DD Genotype on the Risk of Premature Myocardial Infarction

In this association study the authors compared the insertion/deletion (I/D) angiotensin-I converting enzyme (ACE) gene polymorphism in females and males with premature myocardial infarction (MI). I/D ACE gene polymorphism was tested in 738 subjects: 302 patients with MI (151 men and 151 women) and 436 healthy subjects (207 men and 229 women). In women the ACE-DD genotype was not associated with MI (OR 1.1, 95% CI 0.6-2.1, p=0.6), whereas the ACE-DD genotype conferred a 2-fold independent risk for MI in men (95% CI=1.2-3.4; p=0.013) after adjustment for cardiovascular risk factors. The authors found evidence for the sex difference in the effect of the ACE-DD genotype on MI risk. The ACE-DD genotype conferred a 2-fold independent risk for premature MI in males.

Polymorphisms in the promoter region of the basic fibroblast growth factor gene and proliferative diabetic retinopathy in Caucasians with type 2 diabetes

Background:  Basic fibroblast growth factor (bFGF) expression is implicated in proliferative diabetic retinopathy (PDR). The aim of this study was to investigate the association of genetic polymorphisms (−553T/A, −834T/A and −921C/G) in the promoter region of the bFGF gene with PDR in patients with type 2 diabetes. The second aim was to determine whether serum levels of bFGF are affected by genetic factors.

SNP rs2073618 of the osteoprotegerin gene is associated with diabetic retinopathy in Slovenian patients with type 2 diabetes.

Recent studies indicate that osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. Also, a strong association was observed between circulation OPG and microvascular complication. By considering the possible role of OPG in diabetic retinopathy (DR) we examined two of the most studied polymorphisms of the OPG genes rs2073618 (located in exon I) and rs3134069 (located in the promoter region) and their relation to DR in Slovenian patients with type 2 diabetes. Logistic regression analysis demonstrated that the carriers of the CC genotype had a 2.2 higher risk for DR than those with either the CG genotype or the GG genotype (codominant model for rs2073618). Furthermore, the combined effect of single nucleotide polymorphisms (SNPs) rs2073618 and rs3134069 on the DR was stronger than that of each SNP alone. The odds ratio (OR) for individuals with CC genotype (rs2073618) and AA genotype (rs3134069) compared with carriers of CG/GG (rs2073618) + AA (rs3134069) was 2.54 (95% CI = 1.26–5.13, P = 0.01). To conclude, these results indicate that SNPs in the OPG gene may be implicated in the pathogenesis of DR.