Association of Plasminogen Activator Inhibitor (PAI)-1 (SERPINE1) SNPs With Myocardial Infarction, Plasma PAI-1, and Metabolic Parameters

Objective— The purpose of this study was to investigate the effects of plasminogen activator inhibitor-1 (PAI-1) gene (SERPINE1) single nucleotide polymorphisms (SNPs) on the risk of myocardial infarction (MI), on PAI-1 levels, and factors related to the metabolic syndrome. Methods and Results— Eleven SNPs capturing the common genetic variation of the SERPINE1 gene were genotyped in the HIFMECH study. In the 510 male cases and their 543 age-matched controls, a significant gene-smoking interaction was observed. In nonsmokers, the rs7242-G allele was more frequent in cases than in controls (0.486 versus 0.382, P =0.013) whereas the haplotype derived from the rs2227631 (−844A>G)-G and rs2227683-A alleles was ≈3-fold lower in cases than in controls (0.042 versus 0.115, P =0.006). SERPINE1 haplotypes explained 3.5% ( P =0.007) of the variability of PAI-1 levels, which was attributable to the combined effects of 3 SNPs, −844A>G, rs2227666, and rs2227694. The rs6092 (Ala15Thr) and rs7242 SNPs acted additively to explain 4.4% of the variability of plasma insulin levels and 1.6% of the variability of BMI ( P <10 −3 and P =0.023, respectively). Conclusions— SERPINE1 haplotypes are mildly associated with plasma levels of PAI-1 and with the risk of MI in nonsmokers. They are also associated with insulin levels and BMI

Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris

Background: Disturbances of the fibrinolytic system that lead to decreased removal of fibrin deposits may be important risk factors for coronary thrombosis. There is as yet no consensus on the prognostic value of fibrinolytic parameters, which may be attributed in part to the choice of confounding variables controlled for. Methods and Results: The ECAT study is a prospective multicenter study of 3043 patients with angina pectoris followed for 2 years. Baseline measurements included 10 fibrinolytic variables. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. They are presented before and after adjustment for clusters of confounding variables that are markers of different mechanisms: insulin resistance (body mass index, triglyceride, and HDL cholesterol), inflammation (fibrinogen and C-reactive protein), and endothelial cell damage (von Willebrand factor). An increased incidence of events was associated with higher baseline concentrations of tissue plasminogen activator (TPA) antigen (P=.0002), plasminogen activator inhibitor-1 (PAI-1) activity (P=.02), and PAI-1 antigen (P=.001). The associations of PAI-1 activity and PAI-1 antigen with risk of events disappeared after adjustment for parameters reflecting insulin resistance but were not affected by other adjustments. TPA antigen was affected to a similar extent by adjustment for parameters reflecting insulin resistance, inflammation, or endothelial cell damage, but the risk association disappeared only after combined adjustments. Conclusions: The prognostic role of PAI-1 in predicting coronary events is related principally to insulin resistance, whereas that of TPA antigen could be explained only by its relationship with different mechanisms, including insulin resistance, inflammation, and endothelial cell damage. Chemicals/CAS: Biological Markers; Fibrinogen, 9001-32-5; Plasminogen Activator Inhibitor 1; Tissue Polypeptide Antigen; von Willebrand Facto

Incidence of antibiotic resistance in the microbial community of the Tiber River (Rome)

The increased antibiotic use (for humans/animals, in clinics and agriculture) leads to the propagation of resistant variants in microbial communities. This phenomenon has been verified for bacterial communities in water and sediments of Tiber River. The heterotrophic aerobic isolates were checked for resistance to ampicillin, chloramphenicol, streptomycin, sulfadimethoxine and tetracycline. From 1 to 5 resistances were found in more than 80% of isolates. Sulfadimethoxine and tetracycline were ascertained to be the most and the least diffuse resistances, respectively. Resistance incidence is independent from the variation in total microbial count. Multiresistance was also observed, and 5-antibiotic-resistant isolates were mainly found in sediments. The resistance pattern has been explained in term of use and persistence of the different antimicrobial

Contribution of exome sequencing to the identification of genes involved in the response to clopidogrel in cardiovascular patients.

On-clopidogrel platelet reactivity (PR) is associated with the risk of thrombotic or bleeding event in selected populations of high-risk patients. PR is a highly heritable phenotype and a few variants of cytochrome genes, essentially CYP2C19, are associated with PR but only explain 5% to 12% of the variability. The aim of this study is to delineate genetic determinants of on-clopidogrel PR using high-throughput sequencing. We performed a whole exome sequencing of 96 low- and matched high-PR patients in a discovery cohort. Exomes from genes with variants significantly associated with PR were sequenced in 96 low- and matched high-PR patients from an independent replication cohort. We identified 585 variants in 417 genes with an adjusted P value &lt; .05. In the replication cohort, all top variants including CYP2C8, CYP2C18, and CYP2C19 from the discovery population were found again. An original network analysis identified several candidate genes of potential interest such as a regulator of PI3K, a key actor in the downstream signaling pathway of the P2Y &lt;sub&gt;12&lt;/sub&gt; receptor. This study emphasizes the role of CYP-related genes as major regulators of clopidogrel response, including the poorly investigated CYP2C8 and CYP2C18

Interaction between the C-260T polymorphism of the CD14 gene and the plasma IL-6 concentration on the risk of myocardial infarction : the HIFMECH study

Experimental and clinical observations suggest that innate immunity plays a major role in the pathogenesis and progression of atherosclerosis. A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with coronary heart disease. Our objective was to evaluate the contribution of the CD14 polymorphism to the inflammatory response and to the risk of myocardial infarction (MI). We used an European case-control study, the HIFMECH study, comparing 533 men with MI and 575 sex- and age-matched controls. Associations between genotype and disease outcome, according to interleukin-6 (IL-6) and C-reactive protein (CRP) levels, were assessed using conditional logistic regression. The CD14/C-260T polymorphism was associated with plasma IL-6 levels, T/T subjects having higher plasma levels than C/C in cases but not in controls (mean+/-S.D.: 2.04+/-1.37 versus 1.70+/-1.15, p=0.01; 1.20+/-0.75 versus 1.35+/-0.88, p=0.31, respectively). Overall, the CD14/C-260T polymorphism was not associated with the risk of MI. However, in individuals with IL-6 plasma levels in the highest tertile, T allele carriers had a higher risk of MI than C/C (OR: 1.85; CI 95 1.05-3.25). IL-6 increased the risk of MI in carriers of the T allele (OR for first versus third IL-6 tertile: 4.02; CI 95 2.24-7.21), but not in C/C (OR: 0.75; CI 95 0.32-1.74, p=0.004 for interaction). The data indicate a role for CD14/C-260T in MI. The risk mediated by the polymorphism is highly dependent on IL-6 plasma levels