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

PLoS Genetics
Solveig GretarsdottirKari Stefansson

Abstract

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 transcr...Continue Reading

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Citations

Jan 6, 2016·The Journal of Cell Biology·Benoit Chabot, Lulzim Shkreta
May 19, 2016·The New England Journal of Medicine·Paul NioiKari Stefansson
Mar 3, 2017·Nature Genetics·Birte KehrKari Stefansson
May 26, 2017·Journal of Human Genetics·QiPing FengC Michael Stein
May 17, 2018·Journal of the National Cancer Institute·Thorunn RafnarKari Stefansson
Jul 18, 2019·Jornal Vascular Brasileiro·Sandra Maria BarbalhoMarcelo Dib Bechara
Dec 26, 2018·International Journal of Endocrinology and Metabolism·Maryam S DaneshpourFereidoun Azizi
Nov 17, 2016·Nature Reviews. Molecular Cell Biology·Kassie S Manning, Thomas A Cooper
Oct 3, 2018·Communications Biology·Gudjon R OskarssonKari Stefansson
Dec 19, 2018·Circulation. Genomic and Precision Medicine·Laurens F ReeskampG Kees Hovingh
Dec 15, 2020·Circulation. Genomic and Precision Medicine·Eythor BjornssonKari Stefansson

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Methods Mentioned

BETA
genotyping
coronary artery bypass
chips
chip
PCR
RNA-Seq

Software Mentioned

Ensembl Effect Predictor ( VEP
Ensembl
CollectRnaSeqMetrics
HaploReg
Picard
Burrows Aligner ( BWA )
TopHat

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