Type 2 diabetes significantly modulates the cardiovascular risk conferred by the PAI-1 -675 4G/5G polymorphism in angiographied coronary patients.

BACKGROUND: The association of the -675 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene with cardiovascular disease in patients with type 2 diabetes (T2DM) is unknown. METHODS: Genotyping was performed in 672 consecutive Caucasian patients undergoing coronary angiography for the evaluation of stable coronary artery disease (CAD). Vascular events were recorded over 4 years. RESULTS: In non-diabetic subjects (n=524), the homozygous PAI-1 4G4G genotype was significantly associated with significant coronary stenoses>or=50% (adjusted odds ratio (OR) OR=1.84 [1.17-2.92]; p=0.009); however, in T2DM patients (n=148) no such association was observed (OR=0.67 [0.26-1.71]; p=0.401). An interaction term T2DMx4G4G genotype was significant (p=0.006), indicating a significantly stronger association of the polymorphism with CAD in non-diabetic subjects than in patients with T2DM. Also prospectively, the 4G4G genotype conferred an increased risk of vascular events in non-diabetic subjects but not in T2DM patients (hazard ratios 1.76 [1.13-2.74]; p=0.014 and 0.68 [0.30-1.54]; p=0.360, respectively). Again, the interaction T2DMx4G4G genotype was significant (p=0.018). CONCLUSIONS: Presence of T2DM significantly modulates the vascular risk conferred by the PAI-1 -675 4G/5G polymorphism in angiographied coronary patients.

Scavenger receptor class B type I polymorphisms and peripheral arterial disease.

Genetic variations of the scavenger receptor class B type I (SR-BI) have been demonstrated to be associated with plasma lipid parameters, anthropomorphic parameters, and coronary artery disease. We determined the frequency of 3 single-nucleotide polymorphisms within the SR-BI gene (SCARB1) in 354 patients with peripheral arterial disease (PAD) and 354 controls matched for age, sex, and diabetes and related to lipids and disease state, that is, PAD. SCARB1 combined genotype exon 1/intron 5/exon 8 were found to be associated with plasma total and low-density lipoprotein cholesterol levels, respectively. In terms of disease, a significant risk for PAD was observed in female subjects carrying the common allele of exon 8 (odds ratio, 2.623; 95% confidence interval, 1.321-5.208; P=.003). The variant allele of intron 5 was found to be a risk factor for PAD in men (odds ratio, 2.182; 95% confidence interval, 1.288-3.698; P=.005). Furthermore, the SCARB1 combined genotype intron 5/exon 8 proved predictive for PAD in the whole population (P=.006), which remained significant after correction for traditional risk factors. In conclusion, in the present study population, SCARB1 polymorphisms not only show associations with plasma levels of total and low-density lipoprotein cholesterol, respectively, but also with the risk for PAD.

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 (p(interaction) = 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.

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.

CD14 C-159T and toll-like receptor 4 Asp299Gly polymorphisms in surviving meningococcal disease patients.

BACKGROUND: Carriage of Neisseria meningitidis occurs approximately in 10% of the population, onset of invasive meningococcal disease (IMD) cannot be predicted and differs between ages. It remains unclear, which host factors determine invasion of the bloodstream by the bacteria. Innate immunity has a very important role in the first recognition of invading pathogens. The functional single nucleotide polymorphisms (SNPs) CD14 C-159T and toll-like receptor 4 (TLR4) Asp299Gly have been associated with the risk of gram-negative infections. However, their role in development of IMD still remains unclear. Our aim was to investigate the influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of IMD. METHODOLOGY/PRINCIPAL FINDINGS: It was a retrospective case control study. Surviving Austrian meningococcal disease patients were enrolled by sending buccal swabs for DNA analysis. 185 cases with a proven meningococcal infection and 770 healthy controls were enrolled. In surviving meningococcal disease patients DNA analysis of CD14 C-159T and TLR 4 Asp299Gly polymorphisms was performed, as they are part of the innate immune response to bacterial determinants. CD14 C-159T and TLR4 Asp299Gly SNPs were not significantly associated with the presence of IMD when compared to healthy controls. The odds ratio for CD14 C-159T SNP was 1.14 (95% confidence interval (CI) 0.91-1.43; p = 0.266). In TLR4 Asp 299 Gly SNP the odds ratio was 0.78 (CI 0.47-1.43; p = 0.359). CONCLUSION/SIGNIFICANCE: We could not observe a significant influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of developing IMD in surviving meningococcal disease patients. To our knowledge, this is the first study investigating the influence of the CD14 C-159T SNP on the susceptibility to IMD.

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.