Genetics
A new short-read caller for the KIV-2 repeat region correlates with Lp(a) protein levels and reveals distinct ancestry-specific copy-number distributions (BMC Med Genomics 2024)
Original title: Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk
Plasma Lp(a) level is strongly shaped by copy number of KIV-2, a highly polymorphic 5.5 kbp sub-region of the LPA gene that is difficult to genotype accurately. The authors developed the DRAGEN KIV-2 copy-number caller, which uses short-read whole genome sequencing data, and validated it against optical mapping across 166 WGS samples, finding high accuracy and the ability to phase roughly half of samples. Comparing KIV-2 copy number to 24 previously proposed predictive single nucleotide variants, the authors found many of these SNVs to be ineffective proxies for true KIV-2 copy number. Population analyses, including US-based cohorts, revealed distinct KIV-2 copy-number distributions across European, African, and Hispanic American ancestries, further exposing the limits of SNV-based prediction. KIV-2 copy-number estimates from the new caller correlated significantly with measured Lp(a) protein levels, and phasing proved important for accuracy, offering a more reliable genomic tool for Lp(a) risk assessment across ancestries.
Original abstract
The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.