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. 2015 Sep 1;11(9):e1005379.
doi: 10.1371/journal.pgen.1005379. eCollection 2015 Sep.

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

Free PMC article

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

Solveig Gretarsdottir et al. PLoS Genet. .
Free PMC article


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.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: The authors who are affiliated with deCODE are all employees of deCODE genetics/Amgen Inc.


Fig 1
Fig 1. Overview of non-HDL-C associations in the region around LDLR.
Plot A is a 0.8Mb overview centered on LDLR and plot B is a 70kb overview around the LDLR gene. Black circles show-log10 P as a function of build 36 coordinates for associations with non-HDL-C and red crosses correspond to non-HDL-C associations after adjusting for the four variants rs17248720, rs72658867, rs200238879 and rs17248748 that are indicated by vertical broken lines in plot b. Genes are shown in blue and recombination rates are reported in cM/Mb.
Fig 2
Fig 2. RNA sequencing data from blood demonstrates increased expression and abnormal splicing characterized by intron 14 retention in carriers of the splice region variant rs72658867-A.
A. Normalized average LDLR exon coverage for non-carriers (N = 238, in blue) and heterozygotes (N = 15, in red) of rs72658867-A demonstrates increased expression of LDLR transcripts in heterozygotes by ~22%, P = 0.0075. The X-axis is the exon number corresponding to RefSeq transcript NM_000527 for LDLR. The Y-axis shows the median normalized coverage (normalized for each individual to the total number of aligned reads). The error bars are based on the median absolute deviation within each group and is calculated separately for each exon. B. Using the same samples as in a) preferential intron 14 retention is observed in heterozygous carriers of rs72658867-A (shown in red). The X-axis is the genomic position in Mb (hg18/Build36). The Y-axis is the median count of normalized reads as in a). The structure of all LDLR RefSeq transcript variants is shown. The upper panel shows the full length gene whereas the lower panel shows the exons 13, 14 and 15 and the intron retention in intron 14. C. Quantitation of the proportion of transcripts with intron 14 retention in heterozygotes. The Y-axis corresponds to the proportion of RNA sequencing reads that are spliced from exon 14 to exon 15 (correctly spliced) out of the total number of reads that cover the last base of exon 14 (individuals that do not have coverage at this position are omitted). Median proportion: 1.00 (non-carriers); 0.70 (heterozygotes). Mean proportion: 0.95 (non-carriers); 0.71 (heterozygotes). Mann-Whitney test for location shift gives P = 6.0×10−9.

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The Icelandic part of the study was funded by deCODE/Amgen ( The Danish part of the project was funded by the Lundbeck Foundation and produced by The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp, The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( Further funding came from the Danish Council for Independent Research (Medical Sciences) ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.