Gretarsdottir Solveig, Helgason Hannes, Helgadottir Anna, Sigurdsson Asgeir, Thorleifsson Gudmar, Magnusdottir Audur, Oddsson Asmundur, Steinthorsdottir Valgerdur, Rafnar Thorunn, de Graaf Jacqueline, Daneshpour Maryam S, Hedayati Mehdi, Azizi Fereidoun, Grarup Niels, Jørgensen Torben, Vestergaard Henrik, Hansen Torben, Eyjolfsson Gudmundur, Sigurdardottir Olof, Olafsson Isleifur, Kiemeney Lambertus A, Pedersen Oluf, Sulem Patrick, Thorgeirsson Gudmundur, Gudbjartsson Daniel F, Holm Hilma, Thorsteinsdottir Unnur, Stefansson Kari
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
PLoS Genet. 2015 Sep 1;11(9):e1005379. doi: 10.1371/journal.pgen.1005379. eCollection 2015 Sep.
Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻⁸⁰ and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻⁸ and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.
通过高覆盖度的全基因组测序，并将已识别的变异体插入冰岛大部分人群中进行估算，我们在低密度脂蛋白受体基因（LDLR）中发现了四个与非高密度脂蛋白胆固醇（non-HDL-C）水平和冠状动脉疾病（CAD）相关的独立信号。其中两个信号在与non-HDL-C的关联方面是新发现的，由非编码低频变异体（频率在2%-4%之间）代表，即内含子14中的剪接区域变异体rs72658867-A和内含子1中的rs17248748-T。这两个新的关联在另外三个群体中得到了重复验证。这两个变异体均降低了non-HDL-C水平（rs72658867-A，non-HDL-C效应=-0.44 mmol/l，Padj = 1.1×10⁻⁸⁰；rs17248748-T，non-HDL-C效应=-0.13 mmol/l，Padj = 1.3×10⁻¹²），并对CAD具有保护作用（rs72658867-A，OR = 0.76，Padj = 2.7×10⁻⁸；rs17248748-T，OR = 0.92，Padj = 0.022）。位于内含子14中+5位置（NM_000527:c.2140+5G>A）的LDLR剪接区域变异体rs72658867-A，导致转录过程中内含子14的保留，预计会产生一个缺少受体功能所必需结构域的截短型LDL受体。携带rs72658867-A的染色体产生的转录本中，约一半具有这种内含子保留的特征。同样的变异体也增加了LDLR mRNA的表达，然而，野生型转录本的水平并未超过非携带者。这表明破坏LDL受体的序列变异体可以降低non-HDL-C并预防CAD。
