A3 Explorative Genomics - Genomics of sub clinical atherosclerosis

Coordinator:    Prof. Dr. Stefan Blankenberg                                                            Prof. Dr. Wolfgang Koenig
Institution: Universitätsmedizin Mainz                                                             Universität Ulm
The goal of this project was to conduct genome-wide association studies of genetic variability with intermediate phenotypes of subclinical atherosclerosis. Furthermore, the relationship between genetic variation, gene expression, and intermediate phenotypes has been analyzed in an integrated approach.
The project was carried out jointly between the centers in Hamburg and Ulm/Munich. Datasets were genome-wide association data from approximately 5,000 participants of the Gutenberg Health Study (GHS), and 1,850 participants of the KORA F4 study both using the Affymetrix Human Genome-Wide SNP Array 6.0. Based on these data, genetic analyses were performed with respect to intermediate phenotypes: endothelial function, arterial stiffness, intima-media thickness of the carotid artery, carotid plaque, atrial and ventricular geometry, systolic and diastolic function, as well as various biomarkers such as IL-18, IL-1Ra, MPO, arginine and arginine derivatives and CRP, cystatin C, and the microalbuminuria/urin creatinine ratio (the latter in KORA only). Several gene regions were identified, which probably play a role in the pathophysiology of the corresponding phenotypes. These regions will be characterized in depth in the coming years.
The functional characterization of genes and gene regions identified by these genetic analyses was an additional focus of the project. Here, we have been characterizing a gene region on chromosome 2, which was identified in a genetic analysis of the inflammatory marker IL-18. It was shown that genetic variants within this gene region were associated with changing blood concentration of IL-18 and increased cardiovascular risk. In addition, DNA methylation levels in F4 were determined with the Infinium HumanMethylation450 chip and their association with Il-18 blood levels was tested. Several gene regions were identified, one of which contains a gene related to the gene on chromosome 2 mentioned above.
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