A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease

Eythor Bjornsson; Hannes Helgason; Gisli Halldorsson; Anna Helgadottir; Arnaldur Gylfason; Birte Kehr; Adalbjorg Jonasdottir; Aslaug Jonasdottir; Asgeir Sigurdsson; Asmundur Oddsson; Gudmar Thorleifsson; Olafur Th Magnusson; Solveig Gretarsdottir; Florian Zink; Ragnar P Kristjansson; Margret Asgeirsdottir; Dorine W Swinkels; Lambertus A Kiemeney; Gudmundur I Eyjolfsson; Olof Sigurdardottir; Gisli Masson; Isleifur Olafsson; Gudmundur Thorgeirsson; Hilma Holm; Unnur Thorsteinsdottir; Daniel F Gudbjartsson; Patrick Sulem; Kari Stefansson

doi:10.1093/hmg/ddx123

A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease

Eythor Bjornsson, Hannes Helgason, Gisli Halldorsson, Anna Helgadottir, Arnaldur Gylfason, Birte Kehr, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Asmundur Oddsson, Gudmar Thorleifsson, Olafur Th Magnusson, Solveig Gretarsdottir, Florian Zink, Ragnar P Kristjansson, Margret Asgeirsdottir, Dorine W Swinkels, Lambertus A Kiemeney, Gudmundur I Eyjolfsson, Olof SigurdardottirGisli Masson, Isleifur Olafsson, Gudmundur Thorgeirsson, Hilma Holm, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Patrick Sulem, Kari Stefansson

Research output: Other contribution

Abstract

Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.

Original language	English
Publisher	Oxford University Press
DOIs	https://doi.org/10.1093/hmg/ddx123
Publication status	Published - 15 Jun 2017

Other keywords

Kransæðasjúkdómar
Gen
CAR12
MAB12
Haptoglobins
Coronary Artery Disease
Genes
Lipids/blood

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10.1093/hmg/ddx123

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Bjornsson, E., Helgason, H., Halldorsson, G., Helgadottir, A., Gylfason, A., Kehr, B., Jonasdottir, A., Jonasdottir, A., Sigurdsson, A., Oddsson, A., Thorleifsson, G., Magnusson, O. T., Gretarsdottir, S., Zink, F., Kristjansson, R. P., Asgeirsdottir, M., Swinkels, D. W., Kiemeney, L. A., Eyjolfsson, G. I., ... Stefansson, K. (2017, Jun 15). A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease. Oxford University Press. https://doi.org/10.1093/hmg/ddx123

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abstract = "Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.",

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author = "Eythor Bjornsson and Hannes Helgason and Gisli Halldorsson and Anna Helgadottir and Arnaldur Gylfason and Birte Kehr and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Asgeir Sigurdsson and Asmundur Oddsson and Gudmar Thorleifsson and Magnusson, {Olafur Th} and Solveig Gretarsdottir and Florian Zink and Kristjansson, {Ragnar P} and Margret Asgeirsdottir and Swinkels, {Dorine W} and Kiemeney, {Lambertus A} and Eyjolfsson, {Gudmundur I} and Olof Sigurdardottir and Gisli Masson and Isleifur Olafsson and Gudmundur Thorgeirsson and Hilma Holm and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F} and Patrick Sulem and Kari Stefansson",

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doi = "10.1093/hmg/ddx123",

language = "English",

publisher = "Oxford University Press",

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Bjornsson, E, Helgason, H, Halldorsson, G, Helgadottir, A, Gylfason, A, Kehr, B, Jonasdottir, A, Jonasdottir, A, Sigurdsson, A, Oddsson, A, Thorleifsson, G, Magnusson, OT, Gretarsdottir, S, Zink, F, Kristjansson, RP, Asgeirsdottir, M, Swinkels, DW, Kiemeney, LA, Eyjolfsson, GI, Sigurdardottir, O, Masson, G, Olafsson, I , Thorgeirsson, G, Holm, H, Thorsteinsdottir, U, Gudbjartsson, DF, Sulem, P & Stefansson, K 2017, A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease. Oxford University Press. https://doi.org/10.1093/hmg/ddx123

TY - GEN

T1 - A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease

AU - Bjornsson, Eythor

AU - Helgason, Hannes

AU - Halldorsson, Gisli

AU - Helgadottir, Anna

AU - Gylfason, Arnaldur

AU - Kehr, Birte

AU - Jonasdottir, Adalbjorg

AU - Jonasdottir, Aslaug

AU - Sigurdsson, Asgeir

AU - Oddsson, Asmundur

AU - Thorleifsson, Gudmar

AU - Magnusson, Olafur Th

AU - Gretarsdottir, Solveig

AU - Zink, Florian

AU - Kristjansson, Ragnar P

AU - Asgeirsdottir, Margret

AU - Swinkels, Dorine W

AU - Kiemeney, Lambertus A

AU - Eyjolfsson, Gudmundur I

AU - Sigurdardottir, Olof

AU - Masson, Gisli

AU - Olafsson, Isleifur

AU - Thorgeirsson, Gudmundur

AU - Holm, Hilma

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel F

AU - Sulem, Patrick

AU - Stefansson, Kari

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.

AB - Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.

KW - Kransæðasjúkdómar

KW - Gen

KW - CAR12

KW - MAB12

KW - Haptoglobins

KW - Coronary Artery Disease

KW - Genes

KW - Lipids/blood

KW - Kransæðasjúkdómar

KW - Gen

KW - CAR12

KW - MAB12

KW - Haptoglobins

KW - Coronary Artery Disease

KW - Genes

KW - Lipids/blood

U2 - 10.1093/hmg/ddx123

DO - 10.1093/hmg/ddx123

M3 - Other contribution

C2 - 28398513

PB - Oxford University Press

ER -

A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease

Abstract

Other keywords

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