A comprehensive map of single base polymorphisms in the hypervariable LPA Kringle IV-2 copy number variation region.

Lipoprotein(a) concentrations are among the strongest genetic risk factors for cardiovascular disease and present pronounced inter-ethnic and inter-individual differences. About 90% of lipoprotein(a) variance is controlled by the LPA gene, which contains a 5.6 kb large copy number variation (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% of the LPA coding region currently unaddressed. To allow a complete assessment of 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 ultra-deep sequencing protocol and an easy-to-use variant analysis pipeline (https://github.com/genepi/lpa-pipeline). We sequenced 123 Central-European individuals and additionally reanalyzed public data of 2,504 individuals from 26 populations. We found dozens of 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 applicable also to other similar copy number variable regions, allowing accessing regions, which are not captured by common genome sequencing.