Risk Of Coronary Artery Disease In Type Research Articles

Association between STK11 Gene Polymorphisms and Coronary Artery Disease in Type 2 Diabetes in Han Population in China.

Background. Recent studies indicated that the Serine threonine kinase 11 (STK11), which is a key regulator of the AMP-activated protein kinase (AMPK), plays a crucial role in cardiovascular system. This study aimed to investigate whether genetic variations in the STK11 gene affect the risk of coronary artery disease (CAD) in Chinese type 2 diabetics. Methods. 5 haplotype-tagging single nucleotide polymorphisms (SNPs) were selected, and 288 CAD-positive cases and 159 CAD-negative controls with type 2 diabetes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results. The carriers of minor allele A at rs12977689 had a higher risk of CAD compared to the homozygotes of CC (OR = 1.572, 95% CI = 1.039–2.376, p = 0.035), and the difference was still significant after adjustment for the other known CAD risk factors (OR′ = 1.184, 95% CI′ = 1.036–1.353, p′ = 0.013). Conclusion. Genetic variability at STK11 locus is associated with CAD risk in type 2 diabetes in the Chinese population.

MCP-1, dM2-PK and traditional risk factors for coronary artery disease among type II diabetes patients

Inflammatory markers are considered promising new risk markers for coronary artery disease (CAD) as traditional risk factors have been unable to fully explain the increased risk of CAD in type II diabetes mellitus (T2DM) patients. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, is involved in recruitment of monocytes to the arterial wall. Dimeric pyruvate kinase M2 (dM2-PK), a glycolytic enzyme, is elevated in conditions with high rate of inflammation and proliferation . The objective of the present study was to assess the association of two newer risk factors, MCP-1 and dM2-PK along with various traditional CAD risk factors, with T2DM patients. To the best of our knowledge, there hasn’t been any previous report on MCP-1 and dM2-PK as CAD markers in T2DM patients. Fasting blood samples were taken from N = 300 subjects including N = 100 T2DM patients with CAD, N = 100 T2DM patients without CAD, N = 50 CAD patients without any history of diabetes and N = 50 healthy subjects. Various traditional CAD risk factors i.e. obesity, total body fat, lipid profile and blood pressure were measured using standard procedures. Plasma MCP-1 and dM2-PK were quantitatively estimated by sandwich ELISA. Mean plasma MCP-1 concentration was significantly higher in diabetic patients with CAD than those without CAD. There was no significant difference in the mean plasma dM2-PK concentration among diabetic patients with and without CAD. In multivariate regression analysis, elevated plasma MCP-1 was significant risk factor for CAD in diabetic patients as well as non-diabetic subjects. MCP-1 was found to have a high sensitivity as a CAD marker. However dM2-PK was not significantly associated with CAD in diabetic patients as well as non-diabetic subjects. Among the traditional risk factors, age, duration of diabetes, reduced HDL-cholesterol (both sexes), increased SBP (females) and alcohol consumption (males) were significant risk factors for CAD in T2DM patients. Body mass index(BMI), Waist –Hip Ratio (WHR), percent body fat, cholesterol and LDL-cholesterol were significant risk factors in the non-diabetic subjects but not in diabetic patients. Hence the present study implied that plasma MCP-1, along with traditional risk factors (i.e. age, duration of diabetes and reduced HDL-cholesterol), could be used for identification of T2DM patients at risk of CAD.

Allelic variations of the vitamin D receptor (VDR) gene are associated with increased risk of coronary artery disease in type 2 diabetics: The DIABHYCAR prospective study

AimVitamin D deficiency is associated with coronary artery disease (CAD), and the actions of vitamin D are mediated by binding to a specific nuclear vitamin D receptor (VDR). This study investigated the associations of VDR gene variants with CAD in two cohorts of type 2 diabetes patients. MethodsA cohort of 3137 subjects from the prospective DIABHYCAR study (CAD incidence: 14.8%; follow-up: 4.4±1.3 years) and an independent, hospital-based population of 713 subjects, 32.3% of whom had CAD, were assessed. Three SNPs in the VDR gene were genotyped: rs1544410 (BsmI); rs7975232 (ApaI); and rs731236 (TaqI). ResultsIn the DIABHYCAR cohort, an association was observed between the A allele of BsmI and incident cases of CAD (HR: 1.16, 95% CI: 1.05–1.29; P=0.002). Associations were also observed between BsmI (P=0.01) and TaqI (P=0.04) alleles and baseline cases of CAD. The AAC haplotype (BsmI/ApaI/TaqI) was significantly associated with an increased CAD prevalence at the end of the study compared with the GCT haplotype (OR: 1.12, 95% CI: 1.02–1.28; P=0.04). In a cross-sectional study of the independent hospital-based cohort, associations of ApaI (P=0.009) and TaqI (P=0.03) alleles with CAD were observed, with similar haplotype results (OR: 1.33, 95% CI: 1.03–1.73; P=0.03). ConclusionThe haplotype comprising the minor allele of BsmI, major allele of ApaI and minor allele of TaqI of VDR (AAC) was associated with an increased risk of CAD in type 2 diabetes patients. This effect was independent of the effects of other known cardiovascular risk factors.

Skin Intrinsic Fluorescence Is Associated With Coronary Artery Disease in Individuals With Long Duration of Type 1 Diabetes

OBJECTIVESkin intrinsic fluorescence (SIF) reflects many factors, including the presence of certain advanced glycation end products. We investigated whether SIF was associated with coronary artery disease (CAD) in type 1 diabetes and whether this relationship was independent of renal disease.RESEARCH DESIGN AND METHODSSIF was measured in 112 subjects from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and 60 from MedStar Health Research Institute when mean age and diabetes duration were 48 and 36 years, respectively. Cumulative glycemic exposure (updated mean A1C) represented a mean of 18 years’ follow-up in EDC and 10.3 in MedStar.RESULTSOf the 172 participants, 30 had CAD (15 male and 15 female). SIF levels were higher in those with CAD (P < 0.0001). SIF was strongly associated with CAD (odds ratio [OR] 3.5 [95% CI 2.1–6.1]). After age, duration, and updated mean A1C were controlled for, SIF remained associated with CAD (2.4 [1.3–4.4]), more strongly in men (5.6 [2.1–14.6]) than in women (1.4 [0.61–3.3]). As there was no significant sex interaction, further analyses were conducted combining the sexes. Further accounting for sex and nephropathy status did not improve the model fit, though with nephropathy in the model, the OR for SIF was reduced to 1.7 (95% CI 0.89–3.4).CONCLUSIONSSIF has a significant cross-sectional association with CAD. This association is strongly linked to age and duration and, to a lesser degree, to mean A1C and renal disease. SIF therefore may be a useful overall marker of CAD risk in type 1 diabetes.

Low serum PON1 activity: An independent risk factor for coronary artery disease in North–West Indian type 2 diabetics

The paraoxonase (PON1) gene polymorphisms are known to affect the PON1 activity and coronary artery disease (CAD) risk. Studies done so far have given conflicting results. In the present study, we determined the role of PON1 genetic variants and PON1 activity in the development of CAD in North–West Indian Punjabis, a distinct ethnic group, having high incidence of both CAD and type 2 diabetes. 300 angiographically proven CAD with type 2 diabetics and 250 type 2 diabetics with no clinically evident CAD were enrolled. Serum PON1 activity and genotyping of coding (Q192R, L55M) and promoter (−909G/C, −162A/G, −108C/T) region polymorphisms were carried out and haplotypes were determined using PHASE software.The serum PON1 activity was significantly lower in CAD with type 2 diabetics as compared to diabetics alone (51.0 vs. 114.2nmol/min/ml). In logistic regression model after adjusting for confounding variables, lower PON1 activity was found to be significantly associated with CAD risk in type 2 diabetics with OR being 16.8 (95% CI: 10.2–27.7). The lower serum PON1 activity, irrespective of genotypes and haplotypes is a risk factor for development of CAD in North–West Indian Punjabis with type 2 diabetics.

PPARγ gene C161T substitution alters lipid profile in Chinese patients with coronary artery disease and type 2 diabetes mellitus

BackgroundPeroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor, which regulates gene expression of the key proteins involved in lipid metabolism, vascular inflammation, and proliferation. PPARγ may contribute to attenuating atherogenesis and postangioplasty restenosis. PPARγ C161→T substitution is associated with a reduced risk of coronary artery disease (CAD). Whether or not the gene substitution alters the risk of CAD in type 2 diabetes mellitus (T2DM) patients remains unclear.MethodsA total of 556 unrelated subjects from a Chinese Han population, including 89 healthy subjects, 78 CAD patients, 86 T2DM patients, and 303 CAD combined with T2DM patients, were recruited to enroll in this study. PPARγC161→T gene polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphisms. Plasma levels of lipoproteins, apolipoproteins, glucose, and insulin were measured by ELISA or radioimmunoassay (RIA). The coronary artery lesions were evaluated by coronary angiography.ResultsThe frequency of the 161T allele in CAD, T2DM, and CAD combined with T2DM patients was similar to that observed in the healthy control group. However, in CAD combined with T2DM patients, the group with angiographically documented moderate stenoses had a higher frequency of the 161T allele in comparison to the group with severe stenoses (P < 0.05). Moreover, in CAD with T2DM patients, the triglyceride levels and apoB in CC homozygote carriers were significantly higher than those in "T" allele carriers.ConclusionsPPARγC161→T genotypes weren't significantly associated with the risk of CAD, but were markedly correlated with severity of disease vessels in patients with CAD and T2DM. Furthermore, PPARγC161→T substitution was associated with an altered adipose, but not glucose metabolism. These results indicate that the PPARγ C161→T polymorphism may reduce the risk of severe atherogenesis by modulation of adipose metabolism, especially triglycerides and apoB, in Chinese patients with CAD and T2DM.

Abstract 839: A Common Allele at the GRB14 Locus is Associated with Increased Cardiovascular Risk in Type 2 Diabetes: Evidence from a Pooled DNA GWA Study

Genetics factor have long been recognized as important modulators of the risk of coronary artery disease (CAD) in both the general and the diabetic population. Evidence from our group indicates that some of these genes may act synergistically with the diabetic milieu, resulting into an especially strong effect among diabetic individuals. To search the genome for variants having a major effect on CAD risk in type 2 diabetes (T2D), we conducted a 300K SNP genome-wide association (GWA) study using DNA pools made from 322 CAD-positive and 412 CAD-negative individuals with T2D of European origin from the Joslin Heart Study (JHS). SNPs associated with CAD were found to cluster on chromosomes 2q24, 5p14, 9p21, and 14q31. These association signals were confirmed by genotyping of individual DNA samples, with additive ORs in the 1.4–1.6 range. The signal on chromosome 9p21 corresponded to the CAD locus that had been identified in the general population in the vicinity of the CDKN2A/CDKN2B genes. Of the other three regions emerging from the GWA screen, chromosome 2q24 showed the strongest association with CAD. The most representative SNP at this location (rs631871, additive OR=1.53, 95%CI=1.24–1.88, p=7.5 × 10 −5 ) was placed in the 3′ flanking region of the Growth Factor Receptor-Bound 14 ( GRB14 ) gene, which codes for an adapter protein with inhibitory effects on insulin receptor signaling. A similar association was found between rs631871 and cardiovascular mortality in an independent group of 475 type 2 diabetic patients (mean age at baseline=57±10 y) who were recruited at the Joslin Clinic for genetic studies in 1994–1996. In this cohort, the cumulative 10-year cardiovascular mortality was 28.1% among homozygotes for the risk allele, 20.0% among heterozygotes, and 15.8% among homozygotes for the protective allele (age and sex adjusted additive HR=1.41, 95%CI 1.04–1.90, p=0.026). By contrast, the association with increased cardiovascular risk was not confirmed in this cohort for the signals on 5p14 and 14q31. These findings point to the insulin signaling inhibitor GRB14 as a possible modulator of cardiovascular risk among individuals with T2D.

Tag Polymorphisms at the A20 (TNFAIP3) Locus Are Associated With Lower Gene Expression and Increased Risk of Coronary Artery Disease in Type 2 Diabetes

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-kappaB (NF-kappaB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4-3.8, P = 0.001) and 2.0 (1.3-2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C < or =7.0% and 1.2 for those with A1C >7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30-45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

Antioxidants and coronary artery disease among individuals with type 1 diabetes: Findings from the Pittsburgh Epidemiology of Diabetes Complications Study

Objective Oxidative stress has been implicated in the development of diabetes and cardiovascular disease. We evaluated the effect of serum antioxidants and total antioxidant reserve (TAR) on coronary artery disease (CAD) incidence in type 1 diabetes. Methods Subjects were identified from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) cohort, a 10-year prospective study of childhood-onset type 1 diabetes. Mean age at baseline was 28 and diabetes duration 19 years. Coronary artery disease was defined as physician-diagnosed angina, confirmed MI, stenosis ≥50%, ischemic electrocardiogram (ECG), or revascularization. Controls were gender, age, and diabetes duration (±3 years) matched with cases. Samples and risk factors used in analyses were identified from the earliest exam prior to incidence in cases (54 cases, 67 controls). Results None of the antioxidant measures (α-tocopherol, γ-tocopherol, retinol, TAR) showed protection against incident CAD overall. However, a protective effect of α-tocopherol against CAD was observed among antioxidant supplement users (HR=0.22, 95% CI=0.10–0.49) and in renal disease (HR=0.46, 95% CI=0.23–0.91). Despite similar α-tocopherol concentration, there was no protective effect among nonusers of antioxidant supplements. Conclusions High α-tocopherol levels among patients with renal disease and in those using vitamin supplements were associated with lower CAD risk in type 1 diabetes. The specificity of these effects merits further investigation.

The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients.

Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n = 189) and/or (n = 45) with coronary stenosis <or=50%. No association with CAD was observed for the +45 SNP (P = 0.48). By contrast, a significant association was observed for the +276 SNP, with T/T homozygotes having a lower risk of CAD than carriers of other genotypes (adjusted odds ratio [OR] 0.13 [95% CI 0.037-0.46], P = 0.002). A similarly protective effect of the +276 T/T genotype was observed in 110 case and 45 control subjects for whom the CAD status had been determined by angiography (0.04 [0.006-0.30], P = 0.002). Serum adiponectin, although clearly related to several features of the proatherogenic/insulin-resistant phenotype, was not different between control subjects and CAD patients (26 +/- 17 vs. 25 +/- 13 microg/ml). In conclusion, the +276 G>T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects.

Antibodies to oxidized LDL predict coronary artery disease in type 1 diabetes: a nested case-control study from the Pittsburgh Epidemiology of Diabetes Complications Study.

The pathogenesis of excess cardiovascular risk in type 1 diabetes is unclear. LDL cholesterol is only weakly predictive, and its concentration is often normal in type 1 diabetes. We therefore examined whether markers of LDL oxidation such as antibodies to oxidized LDL (Ab-OxLDL) and LDL-containing immune complexes, rather than LDL concentration, were predictive of coronary artery disease (CAD) in type 1 diabetes. This nested case-control study from an epidemiologic cohort study included 49 incident cases of myocardial infarction (MI), angina, or CAD death and 49 age-, sex-, and duration-matched control subjects. Ab-OxLDL was measured by enzyme immunoassay and the apolipoprotein B (ApoB) content of immune complexes (ApoB-IC) precipitated by polyethylene glycol by immunoelectrophoresis in baseline stored samples. Ab-OxLDL was inversely, and ApoB-IC directly, related to subsequent CAD. In multivariate analyses, Ab-OxLDL remained a significant independent predictor along with previously recognized predictors, hypertension and Beck depression score. In conclusion, oxidation of LDL and the immune response it elicits may play a role in predicting the development of CAD in type 1 diabetes and explain at least some of the enhanced CAD risk in type I diabetes.