Zusammenfassung:
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 Hypertonie und dem Diabetes mellitus Typ II spielen dabei vor allem die Lipidparameter wie der Cholesterin- und der Triglyzerid-Spiegel eine entscheidende Rolle.
Ziel dieser Arbeit war es, genregulatorische Elemente der Lipoproteinlipase und des Apolipoprotein E, die beide eine entscheidende Rolle bei der Hydrolyse von Triglyzeriden spielen, auf Mutationen zu untersuchen, die die Expression dieser Proteine verändern und somit Einfluss auf den Triglyzerid-Spiegel ausüben.
Apolipoprotein E vermittelt die Bindung von Triglyzerid-reichen Lipoproteinen an den VLDL-Rezeptor, die Lipoproteinlipase senkt durch Hydrolyse von Triglyzeriden den Triglyzerid-Spiegel im Blut und erhöht gleichzeitig durch Unterstützung der Übertragung von diversen Lipiden den HDL-Cholesterin-Spiegel. Beide Effekte sind verantwortlich für die insgesamt eher atheroprotektive Wirkung der Lipoproteinlipase im Gefäßbett.
In atherosklerotischen Plaques dagegen entwickelt die LPL atherogene Wirkung, durch Erhöhung der RLP-Konzentration werden die Endothel-Eigenschaften verändert und LDL- und VLDL-Partikel werden in der subendothelialen Matrix der Plaques zurückgehalten, wo sie entscheidend zur Entwicklung der Atherosklerose beitragen.
Die Expression der LPL wird durch ihren Promotor gesteuert, die Expression des Apolipoprotein E in der Leber wird durch die Hepatic Control Regions (HCR) 1 und 2 kontrolliert, in reifen Makrophagen und Adipozyten durch die Multienhancer (ME) 1 und 2.
Wir untersuchten diese Sequenzen in der DNA von 264 Patienten mit einem BMI < 25 kg/m2 des Kollektivs der Marburger KHK-Präventions-Allianz, 134 Patienten hatten erhöhte Triglyzeride (> 150 mg/dl), 130 hatten normale Triglyzeride (< 150 mg/dl). Die Sequenzen wurden zunächst durch eine PCR amplifiziert und anschließend in der DGGE auf Mutationen gescreent, auffällige Proben sowie unauffällige Proben als Kontrolle wurden sequenziert. Aus den Daten der Marburger KHK-Präventions-Allianz entnahmen wir die Lipidprofile, den BMI sowie den Koronarstatus und einige weitere Risikofaktoren der Patienten und werteten sie statistisch auf Unterschiede zwischen Mutations- und Wildtyp-Allelträgern aus.
In den regulatorischen Elementen des Apolipoprotein E konnten wir keine Mutationen nachweisen, diese Sequenzen scheinen stark konserviert zu sein, auch in der Literatur werden keine funktionell relevanten SNPs beschrieben.
Im Promotor der LPL fanden wir 2 bereits in der Literatur vorbeschriebene SNPs,
-93T/G und -95G/T.
-95G/T hatte in der Literatur bei In-vitro-Untersuchungen keine Auswirkungen auf die Aktivität des LPL-Promotors, über die Auswirkungen in-vivo gibt es keine Berichte. Bei unseren insgesamt 6 Patienten, die diesen SNP vorwiesen, war das Allel
-95T assoziiert mit erniedrigten Triglyzeriden und einem leicht erhöhten HDL-Cholesterin (n.s.), beides Hinweise auf eine erhöhte Promotor-Aktivität, kein Unterschied konnte beobachtete werden bezüglich der KHK-Prävalenz.
Über -93T/G gibt es in der Literatur widersprüchliche Aussagen, sowohl eine erhöhte als auch eine erniedrigte Promotor-Aktivität sind beschrieben. In unserem Kollektiv konnten wir diesen SNP 8 mal nachweisen, 6x bei Patienten mit Triglyzeriden > 150 mg/dl, 2 mal bei Patienten mit Triglyzeriden < 150 mg/dl. Tendenziell haben unsere Patienten mit -93G-Allel erhöhte Triglyzeride, so wie es auch in einigen Studien beschrieben wurde, das erhöhte KHK-Risiko sowie das erniedrigte HDL-Cholesterin konnten wir bei unseren Patienten nicht nachweisen, genauso wenig wie eine Prädisposition für einen höheren BMI.
Obwohl in den letzten Jahren intensiv über die Bedeutung des Apolipoprotein E und der Lipoproteinlipase für den Triglyzerid-Stoffwechsel und das KHK-Risiko geforscht wurde, bleiben immer noch viele Fragen offen, die es in weiteren Studien und Funktionsuntersuchungen zu klären gilt.
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