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.
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Solveig
S
Gretarsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Hannes
H
Helgason
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Anna
A
Helgadottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Asgeir
A
Sigurdsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Gudmar
G
Thorleifsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Audur
A
Magnusdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Asmundur
A
Oddsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Valgerdur
V
Steinthorsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Thorunn
T
Rafnar
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Jacqueline
J
de Graaf
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran.
Maryam S
MS
Daneshpour
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran.
Mehdi
M
Hedayati
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran.
Fereidoun
F
Azizi
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Niels
N
Grarup
Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark; Faculty of Medicine, University of Aalborg, Aalborg, Denmark; Institute of Public Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
Torben
T
Jørgensen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Henrik
H
Vestergaard
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Torben
T
Hansen
The Laboratory in Mjodd, RAM, Reykjavik, Iceland.
Gudmundur
G
Eyjolfsson
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
Olof
O
Sigurdardottir
Department of Clinical Biochemistry, Landspitali, National University Hospital, Reykjavik, Iceland.
Isleifur
I
Olafsson
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Lambertus A
LA
Kiemeney
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Oluf
O
Pedersen
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Patrick
P
Sulem
Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
Gudmundur
G
Thorgeirsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Daniel F
DF
Gudbjartsson
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
Hilma
H
Holm
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Unnur
U
Thorsteinsdottir
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Kari
K
Stefansson
D002784:Cholesterol / Q000097:blood*; D003324:Coronary Artery Disease / Q000517:prevention & control*; D006801:Humans; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*
D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol