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.

中文翻译：

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短读长测序综合分析LPA基因遗传变异

脂蛋白(a) [LP(a)]是心血管疾病的危险因素，主要受复杂的LPA基因调控。我们研究了 LPA 基因的变异类型及其对 LP(a) 浓度的预测性能。我们使用 DRAGEN LPA Caller (DLC) 和基于读取深度的 CN 估计器在 GENESIS-HD 研究的 8351 个全基因组测序样本中确定了 Kringle IV-2 型 (KIV-2) 拷贝数 (CN)。使用 GangSTR 和 ExpansionHunter 对启动子区域的五核苷酸重复进行基因分型。 LP(a) 浓度可在 4861 名基于人群的受试者中获得。使用随机森林研究了 LP(a) 浓度的预测性能。两个专门呼叫者之间的 KIV-2 CN 一致性很高（r=0.9966；95% 置信区间 [CI] 0.9965-0.9968）。使用 DLC，可以在 47.0% 的受试者中确定等位基因特异性 KIV-2 CN。与总 KIV-2 CN 相比，通过等位基因特异性 KIV-2 CN 可以更好地预测 Lp(a) 浓度。两个单核苷酸变异 4925G>A 和 rs41272114 进一步改善了预测。可以对遗传复杂的 LPA 基因进行分析，并且不同调用者之间的一致性非常好。等位基因特异性 KIV-2 CN 对于预测 LP(a) 浓度比总 KIV-2 CN 更重要。重要的是，等位基因特异性 KIV-2 CN 在所有受试者中都是可测定的。