A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease. / 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; Jørgensen, Torben; Vestergaard, Henrik; Hansen, Torben; Eyjolfsson, Gudmundur; Sigurdardottir, Olof; Olafsson, Isleifur; Kiemeney, Lambertus A; Pedersen, Oluf; Sulem, Patrick; Thorgeirsson, Gudmundur; Gudbjartsson, Daniel F; Holm, Hilma; Thorsteinsdottir, Unnur; Stefansson, Kari.
In: P L o S Genetics, Vol. 11, No. 9, e1005379, 09.2015.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease
AU - Gretarsdottir, Solveig
AU - Helgason, Hannes
AU - Helgadottir, Anna
AU - Sigurdsson, Asgeir
AU - Thorleifsson, Gudmar
AU - Magnusdottir, Audur
AU - Oddsson, Asmundur
AU - Steinthorsdottir, Valgerdur
AU - Rafnar, Thorunn
AU - de Graaf, Jacqueline
AU - Daneshpour, Maryam S
AU - Hedayati, Mehdi
AU - Azizi, Fereidoun
AU - Grarup, Niels
AU - Jørgensen, Torben
AU - Vestergaard, Henrik
AU - Hansen, Torben
AU - Eyjolfsson, Gudmundur
AU - Sigurdardottir, Olof
AU - Olafsson, Isleifur
AU - Kiemeney, Lambertus A
AU - Pedersen, Oluf
AU - Sulem, Patrick
AU - Thorgeirsson, Gudmundur
AU - Gudbjartsson, Daniel F
AU - Holm, Hilma
AU - Thorsteinsdottir, Unnur
AU - Stefansson, Kari
PY - 2015/9
Y1 - 2015/9
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pgen.1005379
DO - 10.1371/journal.pgen.1005379
M3 - Journal article
C2 - 26327206
VL - 11
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 9
M1 - e1005379
ER -
ID: 147661865