Division of Genetic Epidemiology Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
J Lipid Res. 2019 Jan;60(1):186-199. doi: 10.1194/jlr.M090381. Epub 2018 Nov 9.
Lipoprotein (a) [Lp(a)] concentrations are among the strongest genetic risk factors for cardiovascular disease and present pronounced interethnic and interindividual differences. Approximately 90% of Lp(a) variance is controlled by the gene, which contains a 5.6-kb-large copy number variation [kringle IV type 2 (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 coding region currently unaddressed. To completely assess the variability in , 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 ultradeep sequencing protocol, and an easy-to-use variant analysis pipeline. We sequenced 123 Central-European individuals and reanalyzed public data of 2,504 individuals from 26 populations. We found 14 different 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 also applicable to other similar copy number variable regions, allowing access to regions that are not captured by common genome sequencing.
脂蛋白(a)[Lp(a)]浓度是心血管疾病最强的遗传风险因素之一,存在明显的种族间和个体间差异。大约 90%的 Lp(a)变异由基因控制,该基因包含一个 5.6kb 大小的拷贝数变异[Kringle IV 型 2(KIV-2)重复],可产生>40 种蛋白异构体。KIV-2 区域内的变体在常见的测序项目中不被调用,导致目前高达 70%的编码区域未被涉及。为了全面评估的变异性,我们为该区域开发了一种测序策略,并在此报告 KIV-2 区域遗传变异的第一张图谱、一个经过全面评估的超深度测序方案以及一个易于使用的变体分析管道。我们对 123 名中欧个体进行了测序,并重新分析了来自 26 个群体的 2504 名个体的公共数据。我们发现了 14 种不同的无功能和剪接位点突变,以及>100 种,部分甚至常见的错义变体。一些编码变体在一个群体中很常见,但在其他群体中不存在。这为解释 Lp(a)浓度的巨大种族和个体差异提供了新的候选基因。重要的是,我们的方法和管道也适用于其他类似的拷贝数可变区域,使人们能够访问常见基因组测序无法捕获的区域。
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