The ABCA1 gene polymorphisms rs1800977 and rs2230806 are differentially associated with the risk for myocardial infarction in Slovenian subjects with type 2 diabetes mellitus.

BACKGROUND: The adenosine triphosphate-binding cassette transporter A1 (ABCA1) is closely linked to various aspects of the regulation of whole-body cholesterol metabolism and atherosclerosis formation. The object of the study was to investigate the association between rs1800977 and rs2230806 polymorphisms in the ABCA1 gene and myocardial infarction (MI) in Slovenian subjects with type 2 diabetes mellitus (T2DM). METHODS: 1590 T2DM patients (484 subjects with MI and 1106 controls) were included in this retrospective cross-sectional case-control study. After genotyping, Pearson χ2 test was used to compare the distribution of genotypes and alleles among the two groups. Logistic regression analysis adjusted for several risk factors for MI was performed. RESULTS: Genotype distribution showed significant association with MI in T2DM subjects for both selected polymorphisms in ABCA1 gene (p = 0.009 for rs2230806 and p = 0.042 for rs1800977). After applying corrections for confounding variables like age, waist circumference, diastolic blood pressure, serum high-density lipoprotein levels, gender and smoking several genetic models still showed significant associations with MI (dominant model for rs2230806 and dominant, overdominant and co-dominant for rs1800977). CONCLUSION: Our study showed that presence of the T allele of the rs2230806 ABCA1 gene is associated with higher risk of MI, while the A allele of the rs1800977 conferred protection against MI in Slovenian T2DM subjects.

The GG genotype of erythropoietin rs1617640 polymorphism affects the risk of proliferative diabetic retinopathy in Slovenian subjects with type 2 diabetes mellitus: enemy or ally?

PURPOSE: The aim of this study was to investigate the relationship between erythropoietin rs1617640 polymorphism and proliferative diabetic retinopathy (PDR) in Slovenian subjects with type 2 diabetes mellitus. The second aim was to find whether erythropoietin expression in fibrovascular membranes varies among individuals carrying different genotypes of the rs1617640. METHODS: This was a retrospective cross-sectional study based on 797 unrelated Slovenian (Caucasian) participants with type 2 diabetes mellitus. The study group consisted of 217 cases with PDR and 580 controls without clinical signs of diabetic retinopathy. Each subject was genotyped for rs1617640 polymorphism. Fibrovascular membranes from 27 subjects who underwent vitreoretinal surgery were analysed with immunohistochemistry. We searched for expression of erythropoietin, its cognate receptor and for a pan-endothelial marker CD-34. RESULTS: Our results show that subjects carrying a minor GG genotype had significantly higher risk for PDR in both unadjusted (p = 0.02) and adjusted (p = 0.04) recessive genetic models. Subjects with the GG genotype had a 1.6-fold increased risk of developing PDR compared to subjects carrying the major T allele. In fibrovascular membranes from subjects with PDR, the mean number of cells expressing EPO was significantly higher in G allele carriers compared to the homozygotes for the common T allele. CONCLUSION: In Slovenian subjects with type 2 diabetes mellitus, a significant increased risk of PDR was found in GG carriers of the erythropoietin gene rs1617640 polymorphism.

The C allele of the reactive oxygen species modulator 1 (ROMO1) polymorphism rs6060566 is a biomarker predicting coronary artery stenosis in Slovenian subjects with type 2 diabetes mellitus.

BACKGROUND: We aimed to examine the role of the rs6060566 polymorphism of the reactive oxygen species modulator 1 (ROMO1) gene in the development of myocardial infarction (MI) in Caucasians with type 2 diabetes (T2DM). METHODS: A total of 1072 subjects with T2DM were enrolled in this cross-sectional case-control study: 335 subjects with MI and 737 subjects without clinical signs of coronary artery disease (CAD). The genetic analysis of the rs6060566 polymorphism was performed in all subjects. To assess the degree of coronary artery obstruction, a subpopulation of 128 subjects with T2DM underwent coronary computed tomography angiography. Next, endarterectomy samples were obtained during myocardial revascularization from diffusely diseased coronary arteries in 40 cases, which were analysed for ROMO1 expression according to their genotype. RESULTS: There were no statistically significant associations between different genotypes or alleles of the rs6060566 polymorphism and MI in subjects with T2DM. The carriers of the C allele of the ROMO1 rs6060566 had a threefold increased likelihood of having 50-75% coronary artery stenosis (Adjusted OR = 3.27, 95% CI 1.16-9.20). Subjects with two affected coronary arteries had a 3.72 fold higher prevalence of MI (OR = 3.72, 95% CI 1.27-10.84). With CAD in LMCA or LAD, MI prevalence was about 3.5-fold higher (p = 0.07 for LMCA and p = 0.01 for LAD). Furthermore, the carriers of the rs6060566 C allele showed higher number of positive cells for ROMO1 expression in endarterectomy samples of coronary arteries. CONCLUSIONS: According to our study, the rs6060566 polymorphism of the ROMO1 gene is not a risk factor for MI in Caucasians with T2DM. However, we found that subjects carrying the C allele were at a 3.27-fold increased risk of developing severe CAD compared with those who had non-obstructive CAD. Moreover, C allele carriers showed a statistically higher number of cells positive for ROMO1 compared with T allele carriers in coronary endarterectomy samples.

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.