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

• Main Authors: Solveig Gretarsdottir, Hannes Helgason, Anna Helgadottir, Asgeir Sigurdsson, Gudmar Thorleifsson, Audur Magnusdottir, Asmundur Oddsson, Valgerdur Steinthorsdottir, Thorunn Rafnar, Jacqueline de Graaf, Maryam S Daneshpour, Mehdi Hedayati, Fereidoun Azizi, Niels Grarup, Torben Jørgensen, Henrik Vestergaard, Torben Hansen, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Lambertus A Kiemeney, Oluf Pedersen, Patrick Sulem, Gudmundur Thorgeirsson, Daniel F Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, Kari Stefansson
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2015-09-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC4556698?pdf=render

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.