Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.

Aims: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

Methods And Results: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass.

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators.

To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.

Genetic variation in Fc gamma receptor IIa and risk of coronary heart disease: negative results from two large independent populations.

Background: The role of the Fc gamma receptor IIa (Fc gamma RIIa), a receptor for C-reactive protein (CRP), the classical acute phase protein, in atherosclerosis is not yet clear. We sought to investigate the association of Fc gamma RIIa genotype with risk of coronary heart disease (CHD) in two large population-based samples.

Methods: Fc gamma RIIa-R/H131 polymorphisms were determined in a population of 527 patients with a history of myocardial infarction and 527 age and gender matched controls drawn from a population-based MONICA- Augsburg survey.

Determinants of the acute-phase protein C-reactive protein in myocardial infarction survivors: the role of comorbidities and environmental factors.

Background: C-reactive protein (CRP), a sensitive marker of the acute-phase response, has been associated with future cardiovascular endpoints independently of other risk factors. A joint analysis of the role of risk factors in predicting mean concentrations and variation of high-sensitivity CRP (hsCRP) in serum has not been carried out previously.

Methods: We used data from 1003 myocardial infarction (MI) survivors who had hsCRP measured monthly up to 8 times and multivariate mixed effects statistical models to study the role of time-variant and -invariant factors on the geometric mean of and the intraindividual variation in hsCRP concentrations.

Lipoprotein-associated and secretory phospholipase A2 in cardiovascular disease: the epidemiological evidence.

Introduction: Among other lipid related biomarkers, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and type II secretory phospholipase A(2) (sPLA(2)) represent emerging candidates for refined assessment of future cardiovascular disease (CVD) risk. Indeed, emerging evidence from more than prospective 15 studies conducted since 2000, clearly demonstrate the prognostic ability of increased Lp-PLA(2) concentrations or elevated activity for risk of future coronary heart disease (CHD) and stroke. Moreover, Lp-PLA(2) might have similar predictive power for both, incident CHD in initially healthy subjects, as well as for recurrent events in those with clinically manifest atherosclerosis.

RANTES/CCL5 gene polymorphisms, serum concentrations, and incident type 2 diabetes: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.

Objective: Regulated on activation, normal T-cell expressed and secreted (RANTES)/chemokine(C-C motif) ligand (CCL5) is expressed by adipocytes, and serum levels of RANTES are increased in obesity and type 2 diabetes. The aim of this study was to test the hypothesis that RANTES is involved in the pathogenesis of type 2 diabetes by analyzing the triangular association between CCL5 gene polymorphisms, systemic RANTES concentrations, and incident type 2 diabetes in a large prospective study.

Subjects And Methods: The study is based on 502 individuals (293 men and 209 women) and 1632 individuals (859 men and 773 women) with and without incident type 2 diabetes from the population-based MONItoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) case-cohort study respectively (mean follow-up time+/-s.

Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol.

Background: Toll-like receptor 4 (TLR4), the signaling receptor for lipopolysaccharides, is an important member of the innate immunity system. Since several studies have suggested that type 2 diabetes might be associated with changes in the innate immune response, we sought to investigate the association between genetic variants in the TLR4 gene and incident type 2 diabetes.

Methods: A case-cohort study was conducted in initially healthy, middle-aged subjects from the MONICA/KORA Augsburg studies including 498 individuals with incident type 2 diabetes and 1,569 non-cases.

Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.

Objective: Macrophage migration inhibitory factor (MIF), a central cytokine of the innate immunity, has been reported to contribute to the development of cardiovascular disease. MIF is expressed in atherosclerotic lesions in humans, and gene deletion and antibody inhibition studies in animal models indicated that MIF may be cause rather than consequence of atherosclerosis. We sought to assess the triangular association between MIF genotypes, circulating MIF levels and risk for incident coronary heart disease (CHD) in the large, prospective, population-based MONICA/KORA case-cohort study (Augsburg, Southern Germany).

Prospective study of high-sensitivity C-reactive protein as a determinant of mortality: results from the MONICA/KORA Augsburg Cohort Study, 1984-1998.

Background: C-reactive protein (CRP), an exquisitely sensitive systemic marker of inflammation, has emerged as an independent predictor of cardiovascular diseases (CVD). Because other chronic diseases are also associated with an inflammatory response, we sought to assess the association of high-sensitivity CRP (hsCRP) with total and cause-specific mortality in a large cohort of middle-aged men.

Methods: We measured hsCRP at baseline in 3620 middle-aged men, randomly drawn from 3 samples of the general population in the Augsburg area (Southern 0Germany) in 1984-85, 1989-90, and 1994-95.

Variability of serial lipoprotein-associated phospholipase A2 measurements in post myocardial infarction patients: results from the AIRGENE Study Center Augsburg.

Background: Of the numerous emerging biomarkers for coronary heart disease (CHD), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an enzyme involved in lipid metabolism and inflammatory pathways, seems to be a promising candidate. Implementation of Lp-PLA(2) measurement into clinical practice, however, requires data on the reliability of such measurements.

Methods: We measured Lp-PLA(2) concentrations by ELISA in blood samples drawn from 200 post-myocardial infarction patients (39-76 years) at 6 monthly intervals between May 2003 and February 2004, for a total of 1143 samples.

DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: results from the AIRGENE study.

Aims: C-reactive protein represents the classical acute-phase protein produced in the liver in response to inflammatory stimuli. This study evaluated the association of gene polymorphisms with differences in C-reactive protein concentrations and assessed its intra-individual variability as a marker of individual response.

Methods And Results: One thousand and three myocardial infarction (MI) survivors were recruited in six European cities, and C-reactive protein concentrations were measured repeatedly during a 6-month period.

Predicting the risk of cardiovascular disease: where does lipoprotein-associated phospholipase A(2) fit in?

Although an atherogenic lipoprotein phenotype has been well recognized as an important predictor of cardiovascular disease, recent studies have demonstrated a number of additional lipid-related markers as emerging biomarkers to identify patients at risk for future coronary heart disease. Among them, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), seems to be a promising candidate that might be added to the clinical armamentarium for improved prediction of cardiovascular disease in the future. Of particular note, Lp-PLA(2) is the only enzyme that cleaves oxidized low-density lipoprotein (oxLDL) in the subendothelial space, with further generation of proinflammatory mediators such as lysophosphatidylcholine (LysoPC) and oxidized fatty acid (oxFA), thereby probably linking two important features of atherogenesis, namely oxidation of LDL and local inflammatory processes within the atherosclerotic plaque.

Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor for cardiovascular disease. In the present study, plasma levels of Lp-PLA(2) were measured in patients (n=301) admitted to elective coronary angiography because of suspected coronary artery disease (CAD). In a multiple linear regression analysis, the degree of CAD (0-, 1-, 2- or 3-vessel disease) and plasma LDL cholesterol significantly correlated to Lp-PLA(2) levels.

Biomarkers of atherosclerotic plaque instability and rupture.

Basic research over the last two decades has identified a large number of molecules pertinent to the atherosclerotic process, which have clearly improved our understanding of the underlying pathology. It is now well established that inflammation represents a major feature which is present in the vessel wall throughout all stages of the disease until the final pathophysiologic steps, representing plaque destabilization and eventually plaque rupture. Several cells typical for the atherosclerotic plaque, like monocyte-derived macrophages and T-lymphocytes are able to produce and secrete such mediator molecules, like cytokines, chemokines, growth-factors, enzymes, and disintegrins, which lead to activation of endothelial cells, proliferation of smooth muscle cells, lesion progression, and finally to the weakening of a vulnerable plaque by matrix degradation of its fibrous cap.

Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany.

Objectives: We sought to assess the association between serum concentrations of adiponectin and long-term risk of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) in initially healthy middle-aged men within the same representative population in Augsburg, southern Germany.

Background: It has been postulated that high serum concentrations of adiponectin, an emerging biomarker that is linked to insulin resistance and endothelial dysfunction, may be protective against T2DM and CHD.

Methods: Serum concentrations of adiponectin were determined in apparently healthy middle-aged men, sampled from the general population in 1984/1985 and followed until 2002.

Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.

Objective: We performed a prospective case-cohort study in initially healthy, middle-aged men and women from the MONICA/KORA Augsburg studies conducted between 1984 and 2002 to assess the role of IL-18 in comparison with IL-6 and CRP in the prediction of incident coronary heart disease (CHD).

Methods And Results: Concentrations of IL-18 were measured in 382 case subjects with incident CHD and 1980 noncases. Mean follow-up was 11 years.

Biomarkers of outcome from cardiovascular disease.

Purpose Of Review: Recognition of the fact that low-grade local and systemic inflammation accompanies all stages of atherogenesis has led to the identification of a number of novel biomarkers of cardiovascular risk. We highlight recent epidemiological and experimental evidence concerning four emerging biomarkers: C-reactive protein, interleukin-6, D-dimer and white blood cell count.

Recent Findings: Recent epidemiological and experimental data on C-reactive protein, the most extensively studied marker of systemic inflammation, produced in the liver in response to interleukin-6, has cast some doubt on its clinical utility and causal involvement in atherogenesis.

Apolipoprotein A-I and risk for cardiovascular diseases.

Increased concentrations of high-density lipoprotein (HDL) cholesterol have been closely associated with decreased risk of future cardiovascular disease. This protective effect of HDL has been mainly attributed to its involvement in reverse cholesterol transport. More recently, it has been suggested that apolipoprotein A-I (apoA-I), the major protein component of HDL, possesses nearly identical information as HDL in terms of risk prediction for future cardiovascular disease.

Periodontal infections and coronary heart disease: role of periodontal bacteria and importance of total pathogen burden in the Coronary Event and Periodontal Disease (CORODONT) study.

Background: Chronic inflammation from any source is associated with increased cardiovascular risk. Periodontitis is a possible trigger of chronic inflammation. We investigated the possible association between periodontitis and coronary heart disease (CHD), focusing on microbiological aspects.

Association between Lp-PLA2 and coronary artery disease: focus on its relationship with lipoproteins and markers of inflammation and hemostasis.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates pro-inflammatory molecules from oxidized LDL. We examined the association between Lp-PLA2 plasma concentrations and risk of stable coronary artery disease (CAD) in a large case-control study and further assessed the relationship between Lp-PLA2 and various lipid, inflammatory and hemostatic parameters. Lp-PLA2 concentrations were measured in 312 patients with CAD and in 479 age- and gender-matched blood donors.

Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population.

Background: Oxidized LDL (oxLDL) is thought to play a key role in the inflammatory response in the arterial vessel wall.

Methods And Results: In a prospective, nested, case-control study, the association between plasma oxLDL and risk of an acute coronary heart disease (CHD) event was investigated in men without prevalent CHD or diabetes mellitus at baseline. Subjects came from 2 population-based MONICA/KORA Augsburg surveys conducted in the years 1989-1990 and 1994-1995 with follow-up in 1998 (mean+/-SD follow-up time, 5.

Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany.

Background: Chronic inflammation represents an essential feature of the atherosclerotic process. Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme mainly produced by monocytes/macrophages, generates potent proinflammatory products.

Methods And Results: Plasma concentrations of Lp-PLA2 were determined by ELISA in 934 apparently healthy men aged 45 to 64 years sampled from the general population in 1984 and followed up until 1998.

Plasma lipoprotein Lp(a), markers of haemostasis and inflammation, and risk and severity of coronary heart disease.

Background: Elevated plasma (Lp(a)) levels may represent an independent risk factor for atherothrombotic complications but the relation between Lp(a) levels and the extent of coronary artery disease (CHD) has been discussed controversially. Little is known about potential atherothrombogenic mechanisms of Lp(a).

Design: Case-control study.