Polymorphism rs2073618 of the osteoprotegerin gene as a potential marker of subclinical carotid atherosclerosis in Caucasians with type 2 diabetes mellitus.

BACKGROUND: The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor κB ligand/receptor-activator of nuclear factor κB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: 595 subjects with T2DM were enrolled in the cross-sectional study. Subclinical markers of carotid atherosclerosis (carotid intima media thickness, plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment. Genotyping for rs2073618 (a missense variant located in exon I of the OPG gene) was performed, and OPG serum levels were determined by ELISA. RESULTS: Compared to the GG genotype, the CC genotype of the rs2073618 polymorphism had a significantly increased risk for the presence of carotid plaque (OR = 2.54, 95 % CI = 1.22-5.28, p = 0.01). No statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups in subjects with T2DM. Multivariable linear regression analyses in T2DM subjects demonstrated that GC and CC genotypes (p = 0.03 and p = 0.003), together with statin therapy (p = 0.009), were independent predictors of the number of carotid segments with plaques. CONCLUSIONS: Despite the fact that OPG rs2073618 genotypes failed to predict the serum OPG levels as there was no statistical difference among compared genotypes, our results demonstrate that the rs2073618 polymorphism could be a possible genetic marker for the prediction of increased risk for carotid plaque burden as a measure of advanced subclinical atherosclerosis in T2DM subjects.

Polymorphisms XbaI (rs693) and EcoRI (rs1042031) of the ApoB gene are associated with carotid plaques but not with carotid intima-media thickness in patients with diabetes mellitus type 2.

BACKGROUND: Apolipoprotein B is a key structural component of all the atherogenic lipoproteins (LDL, VLDL and IDL). Genetic variations of the ApoB gene may affect plasma ApoB and lipid levels, thus influencing atherogenesis. The present study was designed to investigate the association of polymorphisms XbaI (rs693) and EcoRI (rs1042031) of the ApoB gene with plasma ApoB level, lipid levels and the different ultrasound phenotypes of carotid atherosclerosis in patients with diabetes mellitus type 2. PATIENTS AND METHODS: 595 patients with diabetes (399 on statin therapy and 196 without) and 200 healthy controls were enrolled in the study. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Both XbaI (rs693) and EcoRI (rs1042031) genotypes were determined by real-time PCR. RESULTS: Genotype distributions and allele frequencies of the XbaI and EcoRI polymorphisms were not statistically significantly different between diabetic patients and controls. No statistically significant difference in lipid parameters, ApoA1, ApoB, hs-CRP and fibrinogen as well as CIMT was observed in diabetic patients regarding XbaI and EcoRI polymorphisms, even after adjustment for statin treatment. The risk of having plaques on carotid arteries was higher in homozygous carriers of the mutant X + allele (OR = 1.74, p = 0.03) and lower in diabetics carrying mutant E- alleles (OR = 0.48, p = 0.02). Neither XbaI nor EcoRI polymorphism was associated with CIMT or presence of unstable plaques in diabetic patients. Plasma ApoB level was not independently associated with any of the ultrasonographic parameters of carotid atherosclerosis. CONCLUSIONS: Both XbaI and EcoRI polymorphisms were associated with presence of plaques on carotid arteries but not with CIMT or presence of unstable plaques. Plasma ApoB level was not independently associated with ultrasonographic phenotypes of carotid atherosclerosis in patients with diabetes mellitus.

Phosphoprotein 1 (osteopontin) gene (rs4754) affects markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: Our study was designed to test a possible association between polymorphisms of the SPP1 gene (rs4754, rs28357094) and markers of carotid atherosclerosis (CIMT, number of affected segments of carotid arteries, sum of plaque thickness, presence of carotid plaques, and presence of unstable carotid plaques) in subjects with T2DM. The second aim was to test the possible association between polymorphisms of the SPP1 gene (rs4754, rs28357094) and the progression of carotid atherosclerosis (CIMT progression, change in total plaque thickness, change in the number of sites with plaques) in subjects with T2DM. METHODS: In the prospective study 595 T2DM subjects were enrolled. Markers of carotid atherosclerosis were assessed ultrasonographically. rs4754 and rs28357094 polymorphisms of the phosphoprotein 1 (SPP1) gene were determined with real-time PCR. RESULTS: In our study we found an association between SPP1 rs4754 and the presence of plaques at the time of recruitment, whereas we did not find any association between SPP1 rs28357094 and subclinical markers of carotid atherosclerosis at the time of recruitment. Moreover, we did not find any statistically significant effect of either rs4754 or rs28357094 on subclinical markers of carotid atherosclerosis progression (CIMT progression, change in total plaque thickness, change in the number of sites with plaques). As shown by the multiple linear regression analysis, genotypes of either rs4754 or rs28357094 did not have a statistically significant effect on the progression of subclinical markers of carotid atherosclerosis (CIMT progression, change in total plaque thickness, change in the number of sites with plaques) after the adjustment for confounding variables. CONCLUSIONS: We demonstrated an important effect of the SPP1 rs4754 on subclinical markers of carotid atherosclerosis in subjects with T2DM; however, as demonstrated by the multiple linear regression analysis, neither rs4754 nor rs28357094 had an important impact on the progression of subclinical markers of carotid atherosclerosis in subjects with T2DM.

SOX6 gene polymorphism (rs16933090) and markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: The present study was designed to investigate the association between the polymorphism of the SOX6 gene (rs16933090) and subclinical markers of carotid atherosclerosis, such as carotid intima media thickness (CIMT), the number of affected segments of carotid arteries and the sum of plaque thickness in patients with type 2 diabetes mellitus (T2DM). The second aim of the study was to demonstrate an association between the rs16933090 and subclinical markers of coronary artery disease in the same subset of patients with T2DM. METHODS: A total of 595 T2DM subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed by ultrasonography. Additionally, in a subset of subjects with T2DM a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of SOX6 gene (rs16933090) was performed using KASPar assays. RESULTS: In our study we demonstrated the effect of the rs16933090 on coronary calcium score obtained at CCTA, whereas we did not demonstrate any association between the tested polymorphism (rs16933090) and the presence of more than 50% stenotic lesions in coronary arteries, the sum of plaque thickness, the number of involved carotid segments, high-sensitivity C-reactive protein, the presence of carotid plaques, and the presence of unstable carotid plaques. CONCLUSIONS: In our study, we demonstrated the effect of the rs16933090 on coronary calcium score obtained at CCTA, whereas we did not demonstrate an important effect of the rs16933090 on either subclinical markers of carotid atherosclerosis or the presence of more than 50% stenotic lesions in coronary arteries in Caucasians with T2DM. We presume that the rs16933090 plays a minor role in the development of subclinical atherosclerosis in subjects with T2DM.

Vascular Endothelial Growth Factor Gene Polymorphism (rs2010963) and Its Receptor, Kinase Insert Domain-Containing Receptor Gene Polymorphism (rs2071559), and Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus.

Background. The current study was designed to reveal possible associations between the polymorphisms of the vascular endothelial growth factor (VEGF) gene (rs2010963) and its receptor, kinase insert domain-containing receptor (KDR) gene polymorphism (rs2071559), and markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Genotyping of VEGF/KDR polymorphisms (rs2010963, rs2071559) was performed using KASPar assays. Results. Genotype distributions and allele frequencies of the VEGF/KDR polymorphisms (rs2010963, rs2071559) were not statistically significantly different between diabetic patients and controls. In our study, we demonstrated an association between the rs2071559 of KDR and either CIMT or the sum of plaque thickness in subjects with T2DM. We did not, however, demonstrate any association between the tested polymorphism of VEGF (rs2010963) and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP, the presence of carotid plaques, or the presence of unstable carotid plaques. Conclusions. In the present study, we demonstrated minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM.

Polymorphisms of the PPAR-γ (rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus.

Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays. Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis. Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM.