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Titel:Mutationssuche in regulatorischen Sequenzen der Gene der Apolipoproteine AI, AIV und CIII mithilfe der denaturierenden Gradientengelelektrophorese
Autor:Stünckel, Malte Kristof
Weitere Beteiligte: Renz, Harald (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0637
URN: urn:nbn:de:hebis:04-z2013-06373
DOI: https://doi.org/10.17192/z2013.0637
DDC:610 Medizin
Titel (trans.):Search for mutations in regulatory sequences of the apolipoprotein AI, AIV and CIII genes using the denaturing gradient gel electrophoresis
Publikationsdatum:2013-11-06
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Denaturierende Gradientengelelektrophorese, lipoprotein metabolism, Apolipoprotein, triglycerides, denaturing gradient gel electrophoresis, polymerase chain reaction, Lipoproteinstoffwechsel, Triglyceride, apolipoprotein, Polymerase-Kettenreaktion, Koronare Herzkrankheit

Zusammenfassung:
Adipositas und hohe Triglyzeridkonzentrationen sind neben erhöhten LDL-, Cholesterin- und Lipoprotein(a)- sowie niedrigen HDL-Spiegeln, Diabetes mellitus, Nikotinkonsum, arterieller Hypertonie, hohem Alter und familiärer Prädisposition anerkannte Risikofaktoren für die Entwicklung einer koronaren Herzkrankheit (KHK). Im Allgemeinen führt eine Adipositas zu einer verstärkten Freisetzung von freien Fettsäuren und darüber zu einer Hypertriglyzeridämie. Es gibt jedoch noch eine Vielzahl anderer Ursachen für eine Hypertriglyzeridämie, und einige Patienten entwickeln eine Hypertriglyzeridämie auch bei relativ gering ausgeprägter Adipositas. Die Apolipoproteine AI, AIV und CIII spielen sowohl im Cholesterin- als auch im Triglyzeridstoffwechsel Schlüsselrollen. Ihre regulatorischen Genabschnitte, die Promoter und Enhancer, sind unerlässlich für ihre Expression. Die vorliegende Arbeit sollte untersuchen, ob Mutationen im ApoAI, ApoAIV oder ApoCIII Promoter, sowie dem ApoCIII Enhancer eine Erklärung für einen niedrigen BMI bei gleichzeitig erhöhtem Triglyzeridspiegel bieten können. Zu diesem Zweck wurde zunächst eine Fall-Kontroll-Studie entworfen, um einen Zusammenhang zwischen eventuellen häufigen Mutationen und der BMI-Triglyzerid-Konstellation belegen zu können. Die Zielabschnitte der DNA der gesamten Studienpopulation wurden dann auf Mutationen gescreent. Dazu wurden 264 EDTA-Blut-Proben von Patienten der Marburger Präventionsallianz in eine Fallgruppe (BMI unter 25kg/m2 und Triglyzeridplasmaspiegel über 150mg/dl, 134 Proben) und eine Kontrollgruppe (BMI unter 25kg/m2 und Triglyzeridplasmaspiegel unter 150mg/dl, 130 Proben) eingeteilt. Die DNA der Probanden wurde isoliert und mittels Polymerasekettenreaktion amplifiziert. Die Amplifikate wurden mithilfe der denaturierenden Gradientengelelektrophorese (DGGE) auf Auffälligkeiten im Laufverhalten untersucht. Die DGGE wurde vielfach als das zurzeit effektivste Screeningverfahren zur Mutationssuche mit einer Sensitivität von etwa 95% und der Möglichkeit, relativ viele Proben zeitgleich zu untersuchen, beschrieben. In der DGGE detektierte auffällige Proben wurden sequenziert. Die untersuchten Abschnitte sind in einem gemeinsamen Gencluster auf dem langen Arm des Chromosoms 11 organisiert. Die hier untersuchte Sequenz des ApoAI Promoters umfasste 229bp zwischen den Nukleotiden 116708439 bis 116708667 (-329 bis -101 in Bezug auf den Transkriptionsstart). Die untersuchte ApoAIV Promotersequenz umfasste 437bp zwischen den Nukleotiden 116693995 bis 11669444231 (-439 bis -3). Die ApoCIII Promotersequenz umfasste 226bp zwischen den Nukleotiden 116700604 bis 116700351 (-251 bis -26). In allen Bereichen gibt es vereinzelte bekannte Mutationen, deren Bedeutung jeweils noch nicht geklärt ist. Lediglich im ApoCIII Enhancergen (hier untersucht: 340bp zwischen den Nukleotiden 116700210 bis 116699819, -800 bis -471) gibt es mehrere Polymorphismen, deren Auswirkungen in Studien belegt werden konnten. Im Rahmen dieser Arbeit konnten wir eine Mutation (-63C-->G) im ApoAIV Promotergen nachweisen. Diese wurde mittlerweile unter anderem durch das 1000Genome-Projekt validiert und als rs5090 veröffentlicht. Die in anderen Arbeiten beobachtete, durchweg sehr hohe Sensitivität der DGGE ließ sich in dieser Arbeit nicht bestätigen. Trotz einer beschriebenen C-Allelfrequenz des rs5090-SNP von 4 bis 6%, fand sich in 264 Proben lediglich eine Mutation. Weder bei den Kontrollpersonen noch bei den Patienten mit Hypertriglyzeridämie fanden sich weitere Mutationen. Weitere Studien sollten folgen, um zum Beispiel in einem Expressionsmodell die Relevanz der gefundenen Mutation zu überprüfen.

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