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Genetics of Lipoprotein(a)

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Lipoprotein(a)

Part of the book series: Contemporary Cardiology ((CONCARD))

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Abstract

Lipoprotein(a) (Lp(a)) is a macromolecular complex consisting of LDL and the characteristic apolipoprotein(a)(apo(a)). Lp(a) occurs as a quantitative genetic trait with extremely skewed distributions of levels which range from absent to >200 mg/mL in human plasma from healthy individuals. The major gene controlling the quantitative Lp(a) trait is LPA which codes for apo(a). Two major types of variation in the gene determine Lp(a) levels. First, a variable number of tandem KIV-2 repeats (KIV-2 VNTR) in LPA which are transcribed and translated into protein resulting in an isoform polymorphism of apo(a). The number of KIV-2 repeats (from 1 to >40) and the size of isoforms correlate inversely with Lp(a) levels. Second, several SNPs in LPA some of which result in null alleles. The high number of KIV-2 VNTR alleles and SNPs affecting Lp(a) levels occur in different combinations resulting in an allelic series of numerous haplotypes with individual effects on Lp(a) levels. The two alleles in an individual determine its Lp(a) concentration in a codominant manner. The types and frequency distribution of LPA haplotypes determine the distribution of Lp(a) levels in a population and the different median concentrations and level distributions between populations. SNPs in other genes, e.g., APOE and APOH, have only minor effects on Lp(a) levels but some rare mutations, e.g., in the LDLR gene may have strong effects in an affected individual/family.

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Acknowledgments

I thank Anita Neuner for help with the literature, Eugen Preuss for preparing figures, and Florian Kronenberg for his support and for critically reading the manuscript.

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  1. Institute for Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria

    Gerd Utermann

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  1. Mater Hospital, University of Queensland, Brisbane, QLD, Australia

    Karam Kostner

  2. Medical University of Graz, Graz, Austria

    Gerhard M. Kostner

  3. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

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Utermann, G. (2023). Genetics of Lipoprotein(a). In: Kostner, K., Kostner, G.M., Toth, P.P. (eds) Lipoprotein(a). Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-24575-6_3

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