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

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  • 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
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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.

Original languageEnglish
JournalP L o S Genetics (Online)
Volume11
Issue number9
Pages (from-to)e1005379
ISSN1553-7404
DOIs
Publication statusPublished - Sep 2015

ID: 46044364