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Frankfurt am Main, Germany

Kozian D.H.,Sanofi S.A. | Barthel A.,University Tsklinikum Carl Gustav Carus | Cousin E.,Sanofi S.A. | Brunnhofer R.,Sanofi S.A. | And 9 more authors.
Hormone and Metabolic Research

Two strongly correlated polymorphisms located within the gene of the glucokinase regulator protein (GKRP), rs780094 and rs1260326, are associated with increased plasma triglyceride levels and provide a genetic model for the long-term activation of hepatic glucokinase. Because pharmacological glucokinase activators are evaluated for the treatment of diabetes, the aim of the study was to assess if these polymorphisms could provide evidence for an increased cardiovascular risk of long-term glucokinase activation. Therefore, these polymorphisms were tested in 3500 patients of the Ludwigshafen Risk and Cardiovascular Health study, which was designed to assess cardiovascular risk factors. The two variants were associated with a significant increase of both plasma triglycerides (p<0.0001) and VLDL triglyceride levels (p<0.0001). Plasma free fatty acid concentrations were also significantly elevated (p<0.0078). LDL and HDL cholesterol levels were unchanged. No association was found with respect to coronary stenosis, myocardial infarction, left ventricular wall hypertrophy, and hypertension. In conclusion, long-term genetic glucokinase activation by the GKRP polymorphisms was not associated with an increased cardiovascular risk in the study population. © 2010 Georg Thieme Verlag KG Stuttgart. Source

Winkelmann B.R.,ClinPhenomics GmbH | Winkelmann B.R.,Cardiology Group Frankfurt Sachsenhausen | Von Holt K.,Toxicology Consultant | Unverdorben M.,Clinical Research Institute
Biomarkers in Medicine

Genes influence smoking behavior, affect the metabolism of nicotine and specific chemicals produced during combustion, and enhance (or diminish) pathomechanistic pathways associated with the atherogenic potential of smoking, including oxidative stress, its inflammatory burden or procoagulant potential. Genome-wide association studies have revolutionized the search for new functional genetic markers with ever increasing marker density and the precision in identifying new genetic loci without the need for prior knowledge of functional pathways. Nevertheless, the satistical challenge remains to identify the few true positives, the need for replication of findings and the tedious work of identifying functional genetic variants and their mode of action. Genetic variation within a gene or in areas of the genetic code that control the expression of such a gene is far from being understood. Major advances include the detection of large-scale copy-number variants in the human genome and the demonstration of the decisive role of 'miRNA in controlling gene expression. The role of the genomic methylation pattern in controlling the transcription of the underlying genetic sequence and its role in interacting with environmental influences have yet to be explored in depth. Although candidate genes and their genetic variants have been associated with atherosclerosis and cigarette smoking, a major breakthrough has still to be made. © 2010 Future Medicine Ltd. Source

Stojakovic T.,Medical University of Graz | Scharnagl H.,Medical University of Graz | Trauner M.,Medical University of Graz | Pieske B.,Medical University of Graz | And 7 more authors.

Objective: Serum gamma-glutamyl transferase (GGT) seems to be a predictor for coronary artery disease (CAD). The objective of this study was to elucidate the relationship between GGT and total as well as cardiovascular mortality. Methods: Serum levels of GGT were determined in 2556 subjects with and 699 subjects without angiographic evidence of CAD in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Results: Serum GGT was positively associated with male gender, alcohol consumption and markers of the metabolic syndrome (triglycerides, blood pressure, waist circumference and insulin resistance). It was positively related to aspartate aminotransferase, alanine aminotransferase, C-reactive protein, interleukin-6, and negatively related to glutathione and increased age. During a mean follow-up period of 7.75 years, 754 subjects died. Compared with subjects in the lowest quartile of GGT, the unadjusted hazard ratios (95% CI) for all-cause death were 1.2 (0.9-1.5), 1.4 (1.1-1.8) and 1.9 (1.5-2.3), respectively, in other GGT quartiles. Hazard ratios (CI) for death from cardiovascular causes were 1.4 (1.0-2.0), 1.8 (1.4-2.5) and 2.2 (1.6-2.9). After adjustment for age, gender and cardiovascular risk factors GGT remained a significant predictor for total and cardiovascular mortality. In angiographic CAD the predictive value of GGT was also significant and similar to that in the entire cohort. Conclusion: Serum GGT is predictive of all-cause and cardiovascular mortality in individuals with CAD independently of other cardiovascular risk factors. © 2009 Elsevier Ireland Ltd. All rights reserved. Source

Silbernagel G.,Ludwigshafen Risk and Cardiovascular Health Study Nonprofit LLC | Silbernagel G.,University of Tubingen | Kleber M.E.,Ludwigshafen Risk and Cardiovascular Health Study Nonprofit LLC | Kleber M.E.,Synlab Center | And 6 more authors.
Diabetes Care

OBJECTIVE - To study the prognosis of people with newly diagnosed type 2 diabetes as per the American Diabetes Association (ADA) 2010 definition but without diabetes as per the ADA 2009 definition. RESEARCHDESIGNANDMETHODS - A total of 2,002 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study without a history of diabetes were studied. RESULTS - During the follow-up of a mean duration ± SD of 7.7 ± 2.0 years, 346 people died (202 cardiovascular deaths). Subjects with type 2 diabetes as per the ADA 2009 definition (n = 468) had significantly increased all-cause and cardiovascular mortality compared with people without diabetes as per the ADA 2010 definition (both P≤ 0.003). Subjects with type 2 diabetes as per the ADA 2010 definition but without diabetes as per the ADA 2009 definition (n = 150) were at significantly increased risk to die of cardiovascular diseases (P = 0.029). CONCLUSIONS - Use of the ADA 2010 diabetes definition may be instrumental in improving cardiovascular risk stratification in people undergoing coronary angiography. © 2011 by the American Diabetes Association. Source

Silbernagel G.,LURIC Study Nonprofit LLC | Silbernagel G.,University of Tubingen | Rosinger S.,University of Ulm | Grammer T.B.,University of Heidelberg | And 6 more authors.

Objective: Type 2 diabetes represents a major cardiovascular risk factor. However, few studies have addressed the impact of the disease duration on mortality. Thus, we aimed to investigate the predictive value of diabetes duration for all-cause and cardiovascular mortality in subjects undergoing coronary angiography. Methods: We studied 2455 participants of the LUdwigshafen RIsk and Cardiovascular health study (1768 males/687 females). They had a mean±standard deviation (SD) age of 63.1±9.0 years (range: 40.0-79.9) and a mean±SD body mass index of 27.7±4.0kg/m 2. 704 subjects were newly diagnosed with type 2 diabetes according to the 2010 criteria of the American Diabetes Association and 446 subjects had a known history of type 2 diabetes. The mean±SD duration of the follow-up for all-cause and cardiovascular mortality was 7.4±2.3 years. Results: A total of 543 deaths occurred during the follow-up. Among these, 343 were accounted for by cardiovascular diseases. The duration of type 2 diabetes was strongly and positively correlated with all-cause and cardiovascular mortality (both P<. 0.001). The multivariate adjusted hazard ratios (95% confidence intervals) for cardiovascular mortality compared to subjects without diabetes were 1.76 (1.34-2.32), 2.86 (2.00-4.08), 2.96 (1.85-4.74), and 4.55 (3.24-6.39) for subjects with new onset type 2 diabetes and subjects with known type 2 diabetes (duration ≤5, >5 and ≤10, >10 years), respectively. Conclusions: The data emphasise the need to consider the diabetes duration for the prediction of mortality in subjects at intermediate to high cardiovascular risk. © 2012 Elsevier Ireland Ltd. Source

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