A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease

• Published in: PLoS genetics Vol. 11; no. 9; p. e1005379
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2015; Public Library of Science (PLoS)
• Subjects: Cardiovascular disease; Cholesterol; Cholesterol - blood; Cholesterol, HDL; Coronary Artery Disease - prevention & control; Coronary heart disease; Genetic aspects; Genetic variation; Health aspects; Heart attacks; Humans; Low density lipoprotein receptors; Low density lipoproteins; Observations; Prevention; Receptors, LDL - genetics; RNA Splicing; RNA, Messenger - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005379

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.