Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk

Behera, S.; Belyeu, J.; Chen, X.; Paulin, L. F.; Nguyen, N. Q.; Newman, E.; Mahmoud, M.; Menon, V. K.; Qi, Q.; Joshi, P.; Marcovina, S.; Rossi, M.; Roller, E.; Han, J.; Onuchic, V.; Avery, C. L.; Ballantyne, C. M.; Rodriguez, C. J.; Kaplan, R. C.; Muzny, D. M.; Metcalf, G. A.; Gibbs, R.; Yu, B.; Boerwinkle, E.; Eberle, M. A.; Sedlazeck, F. J.

doi:10.1101/2023.04.24.538128

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bioRxiv · 10.1101/2023.04.24.538128

Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk

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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 [~]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.

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Behera, S., Belyeu, J., Chen, X., Paulin, L. F., Nguyen, N. Q., Newman, E., Mahmoud, M., Menon, V. K., Qi, Q., Joshi, P., Marcovina, S., Rossi, M., Roller, E., Han, J., Onuchic, V., Avery, C. L., Ballantyne, C. M., Rodriguez, C. J., Kaplan, R. C., Muzny, D. M., Metcalf, G. A., Gibbs, R., Yu, B., Boerwinkle, E., Eberle, M. A., Sedlazeck, F. J.. 2023-04-27. Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk. https://doi.org/10.1101/2023.04.24.538128

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