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

Solveig Gretarsdottir; Hannes Helgason; Anna Helgadottir; Asgeir Sigurdsson; Gudmar Thorleifsson; Audur Magnusdottir; Asmundur Oddsson; Valgerdur Steinthorsdottir; Thorunn Rafnar; Jacqueline de Graaf; Maryam S Daneshpour; Mehdi Hedayati; Fereidoun Azizi; Niels Grarup; Torben Jørgensen; Henrik Vestergaard; Torben Hansen; Gudmundur Eyjolfsson; Olof Sigurdardottir; Isleifur Olafsson; Lambertus A Kiemeney; Oluf Pedersen; Patrick Sulem; Gudmundur Thorgeirsson; Daniel F Gudbjartsson; Hilma Holm; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1371/journal.pgen.1005379

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

Solveig Gretarsdottir, Hannes Helgason, Anna Helgadottir, Asgeir Sigurdsson, Gudmar Thorleifsson, Audur Magnusdottir, Asmundur Oddsson, Valgerdur Steinthorsdottir, Thorunn Rafnar, Jacqueline de Graaf, Maryam S Daneshpour, Mehdi Hedayati, Fereidoun Azizi, Niels Grarup, Torben Jørgensen, Henrik Vestergaard, Torben Hansen, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur OlafssonLambertus A Kiemeney, Oluf Pedersen, Patrick Sulem, Gudmundur Thorgeirsson, Daniel F Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, Kari Stefansson

Institut for Folkesundhedsvidenskab

12 Citationer (Scopus)

Abstract

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 × 10⁻⁸⁰ and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, P_adj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and P_adj = 2.7 × 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.

Originalsprog	Engelsk
Artikelnummer	e1005379
Tidsskrift	P L o S Genetics
Vol/bind	11
Udgave nummer	9
Antal sider	20
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1005379
Status	Udgivet - sep. 2015

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10.1371/journal.pgen.1005379Licens: CC BY

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Gretarsdottir, S., Helgason, H., Helgadottir, A., Sigurdsson, A., Thorleifsson, G., Magnusdottir, A., Oddsson, A., Steinthorsdottir, V., Rafnar, T., de Graaf, J., Daneshpour, M. S., Hedayati, M., Azizi, F., Grarup, N., Jørgensen, T., Vestergaard, H., Hansen, T., Eyjolfsson, G., Sigurdardottir, O., ... Stefansson, K. (2015). A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease. P L o S Genetics, 11(9), Artikel e1005379. https://doi.org/10.1371/journal.pgen.1005379

Gretarsdottir, S, Helgason, H, Helgadottir, A, Sigurdsson, A, Thorleifsson, G, Magnusdottir, A, Oddsson, A, Steinthorsdottir, V, Rafnar, T, de Graaf, J, Daneshpour, MS, Hedayati, M, Azizi, F, Grarup, N, Jørgensen, T, Vestergaard, H , Hansen, T, Eyjolfsson, G, Sigurdardottir, O, Olafsson, I, Kiemeney, LA, Pedersen, O, Sulem, P, Thorgeirsson, G, Gudbjartsson, DF, Holm, H, Thorsteinsdottir, U & Stefansson, K 2015, 'A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease', P L o S Genetics, bind 11, nr. 9, e1005379. https://doi.org/10.1371/journal.pgen.1005379

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

abstract = "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.",

author = "Solveig Gretarsdottir and Hannes Helgason and Anna Helgadottir and Asgeir Sigurdsson and Gudmar Thorleifsson and Audur Magnusdottir and Asmundur Oddsson and Valgerdur Steinthorsdottir and Thorunn Rafnar and {de Graaf}, Jacqueline and Daneshpour, {Maryam S} and Mehdi Hedayati and Fereidoun Azizi and Niels Grarup and Torben J{\o}rgensen and Henrik Vestergaard and Torben Hansen and Gudmundur Eyjolfsson and Olof Sigurdardottir and Isleifur Olafsson and Kiemeney, {Lambertus A} and Oluf Pedersen and Patrick Sulem and Gudmundur Thorgeirsson and Gudbjartsson, {Daniel F} and Hilma Holm and Unnur Thorsteinsdottir and Kari Stefansson",

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doi = "10.1371/journal.pgen.1005379",

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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

SN - 1553-7390

VL - 11

JO - P L o S Genetics

JF - P L o S Genetics

IS - 9

M1 - e1005379

ER -

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

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