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

作者：Gretarsdottir Solveig^*; Helgason Hannes; Helgadottir Anna; Sigurdsson Asgeir; Thorleifsson Gudmar; Magnusdottir Audur; Oddsson Asmundur; Steinthorsdottir Valgerdur; Rafnar Thorunn; de Graaf Jacqueline; Daneshpour Maryam S; Hedayati Mehdi; Azizi Fereidoun; Grarup Niels; Jorgensen Torben; Vestergaard Henrik; Hansen Torben; Eyjolfsson Gudmundur; Sigurdardottir Olof; Olafsson Isleifur; Kiemeney Lambertus A; Pedersen Oluf; Sulem Patrick; Thorgeirsson Gudmundur

来源：PLoS Genetics, 2015, 11(9): e1005379.

DOI：10.1371/journal.pgen.1005379

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, P-adj = 1.1 x 10(-80) and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, P-adj = 1.3 x 10(-12)) and confer protection against CAD (rs72658867-A, OR = 0.76 and P-adj = 2.7 x 10(-8) and rs17248748-T, OR = 0.92 and P-adj = 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.

• 出版日期2015-9