Stefan Beer

Single nucleotide polymorphisms of TCF7L2 are linked to diabetic coronary atherosclerosis.

Background Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients. Methodology/Principal Findings We genotyped TCF7L2 variants rs7903146, rs12255372, and rs11196205 in a cross-sectional study including 1,650 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable CAD. Significant CAD was diagnosed in the presence of coronary stenoses ≥50%. Variant rs7903146 in the total study cohort was significantly associated with significant CAD (adjusted additive OR = 1.29 [1.09–1.53]; p = 0.003). This association was strong and significant in T2DM patients (n = 393; OR = 1.91 [1.32–2.75]; p = 0.001) but not in non-diabetic subjects (OR = 1.09 [0.90–1.33]; p = 0.370). The interaction risk allele by T2DM was significant (pinteraction = 0.002), indicating a significantly stronger impact of the polymorphism on CAD in T2DM patients than in non-diabetic subjects. TCF7L2 polymorphisms rs12255372 and rs11196205 were also significantly associated with CAD in diabetic patients (adjusted additive OR = 1.90 [1.31–2.74]; p = 0.001 and OR = 1.75 [1.22–2.50]; p = 0.002, respectively). Further, haplotype analysis demonstrated that haplotypes including the rare alleles of all investigated variants were significantly associated with CAD in the whole cohort as well as in diabetic subjects (OR = 1.22 [1.04–1.43]; p = 0.013 and OR = 1.67 [1.19–2.22]; p = 0.003, respectively). Conclusions/Significance These results suggest that TCF7L2 variants rs7903146 rs12255372, and rs11196205 are significantly associated with angiographically diagnosed CAD, specifically in patients with T2DM. TCF7L2 therefore appears as a genetic link between diabetes and atherosclerosis.

Significant impact of chromosomal locus 1p13.3 on serum LDL cholesterol and on angiographically characterized coronary atherosclerosis.

OBJECTIVES Recently, a significant impact of a new locus on chromosome 1p13.3 on serum LDL (low-density lipoprotein) cholesterol and clinical events of coronary artery disease (CAD) was described. Potential associations between variants on this locus and angiographically characterized coronary atherosclerosis are unknown. We therefore aimed at investigating the association of variants of locus 1p13.3 with coronary atherosclerosis. METHODS We performed genotyping of variants rs599839, rs646776, and rs4970834 on chromosome 1p13.3 in a large cohort of 1610 consecutive Caucasian patients undergoing coronary angiography, where lesions of 50% or more were classified as significant. RESULTS Compared to the homozygous common allele the rare alleles of variants rs599839, rs646776, and rs4970834 were significantly associated with decreased serum LDL cholesterol (132+/-40mg/dl vs. 125+/-36mg/dl, P=0.003, 132+/-40mg/dl vs. 124+/-36mg/dl, P<0.001, and 131+/-40mg/dl vs. 125+/-37mg/dl, P=0.005, respectively). Further, carriers of the rare alleles of variants rs599839 and rs646776 were at a significantly lower risk of significant coronary stenoses than subjects who were homozygous for the frequent alleles, with odds ratios (ORs) of 0.78 [0.63-0.96]; P=0.019 and 0.74 [0.60-0.91]; P=0.004, respectively. After multivariate adjustment including LDL cholesterol, the protective effect of the rare allele of variant rs646776, but not of variant rs599839, on CAD risk remained significant (OR=0.77 [0.61-0.98], P=0.034). CONCLUSIONS We conclude that chromosomal locus 1p13.3 is significantly associated with both, serum LDL cholesterol and coronary atherosclerotic lesions.

Evaluation of the association of genetic variants on the chromosomal loci 9p21.3, 6q25.1, and 2q36.3 with angiographically characterized coronary artery disease

OBJECTIVES The chromosomal loci 9p21.3, 6q25.1, and 2q36.3, represented by their respective leading variants rs1333049, rs6922269 and rs2943634, have been linked with a history of coronary artery disease (CAD) by genome-wide association studies. Whereas the association of variant rs1333049 with CAD was analysed in several subsequent studies, replication studies of variants rs6922269 and rs2943634 are missing. Furthermore, no direct association with coronary atherosclerosis has been established. We therefore aimed at investigating the association of the above variants with coronary atherosclerosis. METHODS We performed genotyping in two large cohorts of consecutive Caucasian patients undergoing coronary angiography for the evaluation of suspected or established stable CAD, comprising 671 and 940 patients, respectively, with a total of 1611 subjects. RESULTS In models of dominant inheritance, variant rs1333049 conferred a significantly increased risk of significant coronary stenoses with lumen narrowing >or=50% in both study cohorts, with adjusted odd ratios (OR) of 1.71 (1.15-2.52); p=0.007 and 1.55 (1.10-2.18); p=0.012, respectively. Variant rs6922269 in neither cohort was significantly associated with CAD. Although carriers of the A allele of variant rs2943634 were at an increased risk of significant coronary stenoses in the second cohort (OR=1.41 (1.06-1.88); p=0.018), no such association was found for the first cohort nor for both cohorts combined. CONCLUSION Our data from two populations show that variant rs1333049 is significantly associated with angiographically characterized CAD. In contrast, variant rs6922269 did not show any impact on coronary atherosclerosis. The association between variant rs2943634 and CAD warrants further investigation.

Alanine aminotransferase and gamma-glutamyl transferase are associated with the metabolic syndrome but not with angiographically determined coronary atherosclerosis.

BACKGROUND Recently, elevated liver enzymes have attracted great interest as potential novel markers of cardiovascular risk. Their association with angiographically determined coronary artery disease (CAD) is unknown. METHODS We enrolled 1000 consecutive patients undergoing coronary angiography for the evaluation of suspected or established stable CAD. The metabolic syndrome (MetS) was defined according to ATP-III criteria; significant CAD was diagnosed in the presence of coronary stenoses with lumen narrowing >or=50%. RESULTS Serum alanine aminotransferase (ALT), the ALT/aspartate aminotransferase (AST) ratio, and serum gamma-glutamyl transferase (GGT) were significantly higher in patients with the MetS than in subjects without the MetS (34+/-21 vs. 29+/-20 U/l; p<0.001, 1.16+/-0.39 vs. 1.00+/-0.36 U/l, p<0.001; and 53+/-88 vs. 43+/-57 U/l, p=0.001, respectively) but were similar in patients with significant CAD as in those who did not have significant CAD at angiography (p=0.592; p=0.731, and p=0.716, respectively). Analysis of covariance after multivariate adjustment including alcohol consumption confirmed that ALT, ALT/AST ratio, and GGT were significantly and independently associated with the MetS but not with significant CAD. CONCLUSIONS ALT, the ALT/AST ratio, and GGT are associated with the MetS but not with angiographically determined coronary atherosclerosis.

Relation of Albuminuria to Angiographically Determined Coronary Arterial Narrowing in Patients With and Without Type 2 Diabetes Mellitus and Stable or Suspected Coronary Artery Disease

Albuminuria is associated with atherothrombotic events and all-cause mortality in patients with and without diabetes. However, it is not known whether albuminuria is associated with atherosclerosis per se in the same manner. The present study included 914 consecutive white patients who had been referred for coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Albuminuria was defined as a urinary albumin/creatinine ratio ≥ 30 μg/mg. Microalbuminuria was defined as 30 to 300 μg albumin/mg creatinine, and macroalbuminuria as a urinary albumin/creatinine ratio of ≥ 300 μg/mg. The prevalence of stenoses of ≥ 50% was significantly greater in patients with albuminuria than in those with normoalbuminuria (66% vs 51%; p <0.001). Logistic regression analysis, adjusted for age, gender, diabetes, smoking, hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, body mass index, estimated glomerular filtration rate, and the use of angiotensin-converting enzyme inhibitors/angiotensin II antagonists, aspirin, and statins, confirmed that albuminuria was significantly associated with stenoses ≥ 50% (standardized adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.15 to 2.44; p = 0.007). The adjusted OR was 1.54 (95% CI 1.03 to 2.30; p = 0.034) for microalbuminuria and 2.55 (95% CI 1.14 to 5.72; p = 0.023) for macroalbuminuria. This association was significant in the subgroup of patients with type 2 diabetes (OR 1.66, 95% CI 1.01 to 2.74; p = 0.045) and in those without diabetes (OR 1.42, 95% CI 1.05 to 1.92; p = 0.023). An interaction term urinary albumin/creatinine ratio*diabetes was not significant (p = 0.579). In conclusion, micro- and macroalbuminuria were strongly associated with angiographically determined coronary atherosclerosis in both patients with and those without type 2 diabetes mellitus, independent of conventional cardiovascular risk factors and the estimated glomerular filtration rate.

Roles of the metabolic syndrome, HDL cholesterol, and coronary atherosclerosis in subclinical inflammation

OBJECTIVE The metabolic syndrome (MetS) and coronary artery disease (CAD) frequently coincide; their individual contribution to inflammation is unknown. RESEARCH DESIGN AND METHODS We enrolled 1,010 patients undergoing coronary angiography. Coronary stenoses ≥50% were considered significant. The MetS was defined according to American Heart Association–revised National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS C-reactive protein (CRP) did not differ between patients with significant CAD and subjects without significant CAD (P = 0.706) but was significantly higher in MetS patients than in those without MetS (P < 0.001). The MetS criteria low HDL cholesterol (P < 0.001), large waist (P < 0.001), high glucose (P < 0.001), and high blood pressure (P = 0.016), but not high triglycerides (P = 0.352), proved associated with CRP. When all MetS traits were considered simultaneously, only low HDL cholesterol proved independently associated with CRP (F = 44.19; P < 0.001). CONCLUSIONS CRP is strongly associated with the MetS but not with coronary atherosclerosis. The association of the MetS with subclinical inflammation is driven by the low HDL cholesterol feature.

Prevalence of impaired glucose metabolism in individuals with peripheral arterial disease

BACKGROUND Epidemiologic studies show an extremely high prevalence of type 2 diabetes mellitus (T2DM) and of impaired glucose tolerance (IGT) in patients with coronary artery disease. However, the prevalence of abnormal glucose metabolism in patients with sonographically proven peripheral arterial disease (PAD) is unknown. We aimed at investigating the prevalence of impaired glucose metabolism in patients with PAD. MATERIALS AND METHODS We enrolled 150 consecutive patients (mean age 68 ± 11 years; 108 men and 42 women) who underwent routine duplex sonography for the evaluation of suspected or established PAD and in whom PAD was verified sonographically. Oral glucose tolerance tests were performed in non-diabetic subjects. RESULTS From our patients, 38.7% had type 2 diabetes. Among non-diabetic patients, 26.1% had impaired glucose tolerance (IGT). Among subjects with normal glucose tolerance, 23.5% had IFG. Thus, the overall prevalence of abnormal glucose metabolism was 65.3% in the investigated patients with sonographically proven PAD. CONCLUSIONS In conclusion, abnormal glucose metabolism was present in 65.3% of our consecutive patients with sonographically proven PAD. Routine screening for abnormal glucose metabolism (including oral glucose tolerance tests) in PAD patients is warranted.

Insulin resistance is associated with the metabolic syndrome and is not directly linked to coronary artery disease

BACKGROUND Insulin resistance (IR) is the key feature of the metabolic syndrome (MetS). Its association with directly visualized coronary atherosclerosis is unclear. We hypothesised that insulin resistance is associated with both angiographically determined coronary artery disease (CAD) and with the MetS. METHODS In 986 consecutive patients undergoing coronary angiography for the evaluation CAD, IR was determined by the HOMA index; the MetS was defined according to NCEP-ATPIII criteria; and significant CAD was diagnosed when coronary stenoses ≥50% were present. RESULTS HOMA IR scores were higher in MetS patients than in subjects without the MetS (4.9±6.4 vs. 2.2±2.0; p<0.001). HOMA IR did not differ significantly between patients with significant CAD and those who did not have significant CAD. When both, the presence of MetS and of significant CAD were considered, HOMA IR was significantly higher in patients with the MetS both among those who had significant CAD (4.9±6.8 vs. 2.2±1.8; p<0.001) and among those who did not have significant CAD (5.0±5.8 vs. 2.1±2.3; p<0.001), it did not differ significantly between patients with significant CAD and subjects without significant CAD among patients with the MetS nor among those without MetS. Similar results were obtained with the IDF definition of the MetS. CONCLUSION IR is significantly associated with the MetS but not with angiographically determined CAD. IR may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis.

Type 2 diabetes but not coronary atherosclerosis is an independent determinant of impaired mobility in angiographied coronary patients.

AIMS We aimed at determining the associations of type 2 diabetes (T2DM) and of angiographically determined coronary artery disease (CAD) with impaired mobility. METHODS We enrolled 747 consecutive patients undergoing coronary angiography for the evaluation of stable CAD. Mobility was assessed by the standardized timed-up-and-go (TUG) test, a functional test of physical performance. RESULTS Mobility was impaired (TUG time >10s) in 199 (26.6%) patients. The proportion of subjects with impaired mobility was higher among patients with T2DM than among non-diabetic individuals (40.2% vs. 22.0%; p<0.001), whereas it did not differ significantly between patients with significant coronary stenoses >or=50% and those without such lesions (p=0.802). Multivariate adjustment in logistic regression analyses confirmed that T2DM (adjusted odds ratio (OR)=2.05 [95% CI 1.35-3.11]; p=0.001) but not the presence of significant coronary stenoses (adjusted OR=0.81 [0.55-1.21]; p=0.306) was independently associated with impaired mobility. CONCLUSIONS T2DM but not coronary atherosclerosis is an independent determinant of impaired mobility in the high risk population of angiographied coronary patients. Mobility enhancing exercise programs are needed for diabetic coronary patients.

KEY ROLE OF LOW HDL CHOLESTEROL FOR THE ASSOCIATION OF THE METABOLIC SYNDROME WITH INFLAMMATION IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE

Methods: We enrolled 410 consecutive patients who underwent routine duplex sonography for the evaluation of suspected or established PAD Fontain stages I-III and in whom PAD was verified sonographically. According to National Cholesterol Education Programme Adult Treatment Panel III criteria, the MetS was defined in the presence of at least 3 out of the 5 quantitatively defined criteria large waist circumference, low HDL cholesterol, high triglycerides, high blood pressure, and elevated fasting glucose.