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Lipoproteinstoffwechsel und koronare Herzkrankheit

Modellsysteme für komplexe Erkrankungen

Lipoprotein metabolism and coronary artery disease

Model systems for complex diseases

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medizinische genetik

Zusammenfassung

Untersuchungen von genetischen Störungen des Lipoproteinstoffwechsels und deren Zusammenhang mit der koronaren Herzkrankheit (KHK) haben eine VorreiteroIIe für das Verständnis der Genetik komplexer Erkrankungen gespielt. Sie haben darüber hinaus zur Entwicklung von Medikamenten zur Prävention der Atherosklerose als häufigster Todesursache in den lndustrieländem geführt. So hat die Analyse der familiären Hypercholesterinämie (FH), deren häufigste Ursache Mutationen im LDLR-Gen sind, zur Entwicklung der HMG-CoA-Reduktasehemmer (Statine) beigetragen. Mittlerweile wurden durch genomweite Assoziationsstudien (GWAS) Varianten in über 90 Genen gefunden, die die Konzentrationen von Plasmalipiden beeinflussen. Diese erklären aber nur einen geringen Teil der genetischen Varianz. Am Beispiel des klassischen Apo-E-Polymorphismus wird als ein möglicher Grund für die „missing heritability“ die Auswahl der auf den Arrays repräsentierten SNPs diskutiert und gezeigt, dass Interaktionen dazu führen können, dass Assoziationen von Genotypen mit Erkrankungen übersehen werden. Aufgrund genetischer Untersuchungen nach dem Prinzip der „Mendelian randomization“ ist die pathophysiologische Relevanz einer hohen Lp(a)-Konzentration als Risikofaktor für KHK heutzutage unbestritten. Für Patienten mit terminaler Niereninsuffizienz ist jedoch ein Polymorphismus (KIV-2-CNV) im LPA-Gen ein besserer Prädiktor für die KHK als erhöhte Lp(a)-Konzentrationen im Plasma.

Abstract

A better understanding of complex diseases and their genetics has been gained by investigating genetic disorders of lipoprotein metabolism. This has resulted in the development of ddrugs to prevent atherosclerosis, the most frequent cause of death in industrialized countries. Thus, analysis of familial hypercholesterinemia (FH), the most frequent cause of which are mutations on the LDLR gene, has contributed to the development of HMG-CoA reductase inhibitors (statins). Meanwhile, in genome-wide association studies (GWAS), variants in over 90 genes have been found to influence the concentration of plasma lipids. However, these explain only a small fraction of the genetic variance of the traits. Taking the classical polymorphism of Apo-E as an example, it is discussed that one possible reason for the “missing heritability” may be the selection of the SNPs on the arrays used in the GWAS. Further, this polymorphism demonstrates how interactions may mask a connection between a genotype and a disease. Genetic studies based on the principle of “Mendelian randomization” have established the causal role of a high Lp(a) concentration as a risk factor for coronary heart disease (CHD). For patients with end-stage renal disease, however, a polymorphism (KIV-2 CNV) is a better predictor for CHD than Lp(a) concentration.

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Danksagung

Den zahlreichen Mitarbeitern, die über viele Jahre an den Projekten zum Apo-E-Polymorphismus und zum Lp(a) mitgewirkt haben, gilt mein besonderer Dank. F. Kronenberg danke ich für die kritische Durchsicht des Manuskripts und Kommentare.

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  1. Sektion für Humangenetik, Medizinische Universität Innsbruck, Schöpfstraße 41, A-6020, Innsbruck, Österreich

    G. Utermann

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Utermann, G. Lipoproteinstoffwechsel und koronare Herzkrankheit. medgen 23, 7–14 (2011). https://doi.org/10.1007/s11825-010-0259-3

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