Lipoprotein (a) [LP(a)] is a risk factor for cardiovascular diseases and mainly regulated by the complex LPA gene. We investigated the types of variation in the LPA gene and their predictive performance on LP(a) concentration. We determined the Kringle IV-type 2 (KIV-2) copy number (CN) using the DRAGEN LPA Caller (DLC) and a read-depth based CN estimator in 8351 whole genome sequencing samples from the GENESIS-HD study. The pentanucleotide repeat in the promoter region was genotyped with GangSTR and ExpansionHunter. LP(a) concentration was available in 4861 population-based subjects. Predictive performance on LP(a) concentration was investigated using random forests. The agreement of the KIV-2 CN between the two specialized callers was high (r=0.9966; 95% confidence interval [CI] 0.9965-0.9968). Allele-specific KIV-2 CN could be determined in 47.0% of the subjects using the DLC. Lp(a) concentration can be better predicted from allele-specific KIV-2 CN than total KIV-2 CN. Two single nucleotide variants 4925G>A and rs41272114 further improved prediction. The genetically complex LPA gene can be analyzed with excellent agreement between different callers. The allele-specific KIV-2 CN is more important for predicting LP(a) concentration than the total KIV-2 CN. It would be important that the allele-specific KIV-2 CN is determinable in all subjects.

M.R. is an employee of Illumina. R.T. holds a professorship in clinical cardiology at the University Medical Center Hamburg-Eppendorf, supported by the Kuehne Foundation and reports research support from the German Center for Cardiovascular Research (DZHK), the Joachim Herz Foundation, the Swiss National Science Foundation (Grant No P300PB_167803), and the Swiss Heart Foundation as well as speaker honoraria/consulting honoraria from Abbott, Amgen, Astra Zeneca, Psyros, Roche, Siemens, Singulex and Thermo Scientific BRAHMS. T.Z. is supported by the German Research Foundation, the EU Horizon 2020 programme, the EU ERANet and ERAPreMed Programmes, the German Centre for Cardiovascular Research (DZHK, 81Z0710102), and the German Ministry of Education and Research. S.B., R.T., T.Z., and A.Z. are listed as co-inventors of an international patent on the use of a computing device to estimate the probability of myocardial infarction (International Publication NumberWO2022043229A1). R.T. and T.Z. are shareholders of the ART-EMIS Hamburg GmbH. A.Z. is scientific director and R.O.B. and G.K. are employees of Cardio-CARE, which is shareholder of the ART-EMIS Hamburg GmbH.

We gratefully acknowledge funding of the GENESIS-HD study by the Kuehne Foundation and the measurement of Lp(a) in HCHS by Amgen.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The local ethics committee of the Landesaerztekammer Hamburg (State of Hamburg Chamber of Medical Practitioners, PV5131) had no objections against the conduct of the study. The Data Protection Commissioner of the University Medical Center of the University Hamburg-Eppendorf and the Data Protection Commissioner of the Free and Hanseatic City of Hamburg approved the study. The study is registered at ClinicalTrial.gov (NCT03934957).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data used in this study may not be shared due to privacy issues. The targets file used for the analysis is available in the supplement.