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

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. © 2015 gretarsdottir et al.