Journal of Lipid Research (Jan 2019)

A comprehensive map of single-base polymorphisms in the hypervariable LPA kringle IV type 2 copy number variation region[S]

  • Stefan Coassin,
  • Sebastian Schönherr,
  • Hansi Weissensteiner,
  • Gertraud Erhart,
  • Lukas Forer,
  • Jamie Lee Losso,
  • Claudia Lamina,
  • Margot Haun,
  • Gerd Utermann,
  • Bernhard Paulweber,
  • Günther Specht,
  • Florian Kronenberg

Journal volume & issue
Vol. 60, no. 1
pp. 186 – 199

Abstract

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Lipoprotein (a) [Lp(a)] concentrations are among the strongest genetic risk factors for cardiovascular disease and present pronounced interethnic and interindividual differences. Approximately 90#x0025; of Lp(a) variance is controlled by the LPA gene, which contains a 5.6-kb-large copy number variation [kringle IV type 2 (KIV-2) repeat] that generates >40 protein isoforms. Variants within the KIV-2 region are not called in common sequencing projects, leaving up to 70#x0025; of the LPA coding region currently unaddressed. To completely assess the variability in LPA, we developed a sequencing strategy for this region and report here the first map of genetic variation in the KIV-2 region, a comprehensively evaluated ultradeep sequencing protocol, and an easy-to-use variant analysis pipeline. We sequenced 123 Central-European individuals and reanalyzed public data of 2,504 individuals from 26 populations. We found 14 different loss-of-function and splice-site mutations, as well as >100, partially even common, missense variants. Some coding variants were frequent in one population but absent in others. This provides novel candidates to explain the large ethnic and individual differences in Lp(a) concentrations. Importantly, our approach and pipeline are also applicable to other similar copy number variable regions, allowing access to regions that are not captured by common genome sequencing.

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