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Genetische Analysen als Basis einer individualisierten Medizin bei koronarer Herzkrankheit

Genetic analyses as basis for a personalized medicine in patients with coronary artery disease

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Zusammenfassung

Genomweite Analysen haben das Verständnis der Ätiologie der koronaren Herzerkrankung (KHK) um neue Dimensionen erweitert. Nach aktuellem Stand finden sich bei Westeuropäern 46 chromosomale Loci, die mit genomweiter Signifikanz (d. h. p<5×10-8) mit einem erhöhten Risiko für die KHK assoziiert sind. Da die individuelle DNA-Sequenz schon bei Geburt feststeht und somit die risikobehafteten Varianten nicht erst durch sekundäre Krankheitsprozesse („confounder“) auftreten, kann angenommen werden, dass jedes betroffene Gen in einen primären und damit kausalen Pathomechanismus der KHK eingreift. Interessanterweise lassen sich nur etwa 20% der Effekte, welche durch die neu entdeckten Loci vermittelt werden, durch die Beeinflussung traditioneller Risikofaktoren erklären. Dies impliziert, dass bislang noch unerforschte Mechanismen – und damit potenziell neue therapeutische Angriffsflächen – zur Entstehung der KHK beitragen. Überrascht hat auch die hohe Allelhäufigkeit der bislang entdeckten Risikoallele: Im doppelt angelegten Chromosomensatz tragen Individuen westeuropäischer Abstammung im Durchschnitt 30–50 risikobehaftete Allele an den 46 Loci. Somit besteht bei allen Mitgliedern unserer Population eine mehr oder weniger große genetische Disposition zur KHK. Andererseits ist auch bemerkenswert, dass das genetische Risiko bei vielen Trägern der Risikoallele anscheinend kompensiert werden kann, da selbst im hohen Alter nicht bei jedem eine klinisch manifeste KHK auftritt. Dies weist auf bislang noch unverstandene Gen-Gen- oder Gen-Umwelt-Interaktionen hin und begrenzt die aktuellen Möglichkeiten der individuellen Risikoprädiktion.

Abstract

Knowledge about the etiology of coronary artery disease (CAD) entered new dimensions using genome-wide association studies. The current situation is that 46 chromosomal loci have been identified to be associated with CAD with genome-wide significance, i.e. p<5×10-8, in Western Europeans. As the individual DNA sequence remains unchanged after fertilization, the risk variants cannot occur due to confounders, such as secondary disease processes. Thus, it can be proposed that these variants are directly affecting a primary and thereby causal pathophysiological process in CAD. Interestingly, only 20% of the effects mediated by the identified loci can be explained by the influence of traditional risk factors. This implies that yet unknown mechanisms and, as a consequence, new therapeutic targets play an important role in the pathophysiology of CAD. However, the high allele frequency of risk loci was also surprising. In the diploid chromosome set Western European individuals carry on average 30–50 risk variants at the 46 loci. Considering this, every individual in the population carries a larger or smaller genetic predisposition for CAD. On the other hand it is remarkable that many risk allele carriers seem to be able to compensate the genetic risk: even in old age not everyone suffers from CAD. This indicates yet unknown gene-gene and gene-environment interactions and limits the current possibilities in individual risk prediction.

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Einhaltung ethischer Richtlinien

Interessenkonflikt. T. Kessler, B. Kaess, F. Bourier, J. Erdmann und H. Schunkert geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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Authors and Affiliations

  1. Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Lazarettstr. 36, 80636, München, Deutschland

    T. Kessler, B. Kaess, F. Bourier &  H. Schunkert

  2. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Deutschland

    J. Erdmann

  3. Deutsches Zentrum für Herz-Kreislaufforschung (DZHK e.V.), Standort München (Munich Heart Alliance), München, Deutschland

    H. Schunkert

  4. Deutsches Zentrum für Herz-Kreislaufforschung (DZHK e.V.), Standort Hamburg/Kiel/Lübeck, Hamburg/Kiel/Lübeck, Deutschland

    J. Erdmann

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  1. T. Kessler
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  2. B. Kaess
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  3. F. Bourier
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  4. J. Erdmann
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  5. H. Schunkert
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Correspondence to H. Schunkert.

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Kessler, T., Kaess, B., Bourier, F. et al. Genetische Analysen als Basis einer individualisierten Medizin bei koronarer Herzkrankheit. Herz 39, 186–193 (2014). https://doi.org/10.1007/s00059-013-4048-z

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