Untersuchungen zur Assoziation von Polymorphismen in regulatorischen Elementen der Lipoproteinlipase und des Apolipoprotein E mit KHK und Triglyzerid-Stoffwechsel

Durch Atherosklerose bedingte Kardiovaskuläre Erkrankungen sind die Haupttodesursache in der westlichen Welt. Neben der familiären Disposition, dem Geschlecht und dem Lebensalter gibt es zahlreiche beeinflussbare Risikofaktoren für diese Erkrankungen. Zusätzlich zum Nikotin-Konsum, der arteriellen H...

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Bibliographic Details
Main Author: Schell, Johanna Kristina
Contributors: Schäfer, Jürgen (Prof.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2011
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Cardiovascular diseases caused by atherosclerosis are the major causes of death in the western world. Beside a positive family history, gender and age there are many other risk factors, that can be influenced by mankind. Next to smoking, high blood pressure and Diabetes mellitus these are especially serum cholesterol- and Triglyzerid-level. Lipoprotein lipase and apolipoprotein E are important factors for the hydrolysis of Triglyzerides and in that way they have a big influence on Triglyzerid-level. Aim of this study was to screen certain gene-regulatory sequences of these proteins for mutations that have influence on their expression. Apolipoprotein E mediates the binding of Triglyzerid-rich-lipoproteins to the VLDL-receptor. Lipoprotein lipase lowers Triglyzerid-levels in serum through hydrolysis and raises HDL-level by supporting the exchange of other lipids between lipoproteins. These two effects are responsible for the atheroprotective impact of this enzyme. In atherosclerotic plaques lipoprotein lipase has atherogenic impact by the increase of the amount of remnant lipoproteins which change the endothelial characteristics. LDL and VLDL are kept to the subendothelial matrix and support the progress of atherosclerosis. The expression of lipoprotein lipase is controlled by its promoter, the expression of apolipoprotein E in the liver requires 2 hepatic control regions (HCR1 and HCR2), expression in mature macrophages and adipocytes requires multinenhancer (ME1 and ME2). We studied these sequences in the DNA of 264 patients with an BMI < 25 kg/m2 from the Marburger KHK-Präventions-Allianz. 134 of them had elevated Triglyzerides (> 150 mg/dl), 130 had normal Triglyzerid-levels (< 150 mg/dl). The sequences were first amplified using PCR and then screened for mutations by DGGE, suspicious probes were sequenced. From the data of the Marburger KHK-Präventions-Allianz we took the lipid levels, BMI and the result of the coronary angiography as well as some other risk factors and made a statistical analysis between wildtyp- and mutation-patients. Within the regulatory elements of apolipoprotein E we could not find any mutation, the sequences seem to be strongly conserved, even in literature there are no important mutations described. Within the promoter of the lipoprotein lipase we found 2 already described SNPs, -93T/G and -95G/T. Described studies of -95G/T showed no influence of this SNP on promoter-activity in vitro, and statements on in-vivo-experiments could not be found. In our study we found six carriers of this mutations, the -95T-Allel was associated with lower Triglyzerid-level and moderate elevated HDL-level. Both effects can be seen as hints that -95T eventually increases the promoter-activity. We could not find any differences relating to risk of developing coronary heart disease. Different effects of -93T/G are described in literature, an increased activity as well as a lowered activity. Within our study we had 8 patients with this mutation, two of them had Triglyzerides > 150 mg/dl, two < 150 mg/dl. There was a trend of slightly elevated Triglyzerides as described in other studies, the elevated risk of coronary heart disease and lower HDL-levels as well as an higher BMI could not be confirmed with our data. Also there has been lots of research concerning apolipoprotein E and lipoprotein lipase and their influence on Triglyzerid-level and CHD, there still remain lots of open questions that need to be cleared by further studies.