A rare missense variant in NR1H4 associates with lower cholesterol levels

Aimee M. Deaton; Patrick Sulem; Paul Nioi; Stefania Benonisdottir; Lucas D. Ward; Olafur B. Davidsson; Socheata Lao; Anna Helgadottir; Fan Fan; Brynjar O. Jensson; Gudmundur L. Norddahl; Aslaug Jonasdottir; Adalbjorg Jonasdottir; Asgeir Sigurdsson; Ragnar P. Kristjansson; Asmundur Oddsson; Gudny A. Arnadottir; Hakon Jonsson; Isleifur Olafsson; Gudmundur I. Eyjolfsson; Olof Sigurdardottir; Einar S. Bjornsson; Sigurdur Olafsson; Thora Steingrimsdottir; Thorunn Rafnar; Gudmundur Thorgeirsson; Gisli Masson; Gudmar Thorleifsson; Daniel F. Gudbjartsson; Hilma Holm; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1038/s42003-018-0015-9

A rare missense variant in NR1H4 associates with lower cholesterol levels

Aimee M. Deaton, Patrick Sulem^*, Paul Nioi, Stefania Benonisdottir, Lucas D. Ward, Olafur B. Davidsson, Socheata Lao, Anna Helgadottir, Fan Fan, Brynjar O. Jensson, Gudmundur L. Norddahl, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Asgeir Sigurdsson, Ragnar P. Kristjansson, Asmundur Oddsson, Gudny A. Arnadottir, Hakon Jonsson, Isleifur Olafsson, Gudmundur I. EyjolfssonOlof Sigurdardottir, Einar S. Bjornsson, Sigurdur Olafsson, Thora Steingrimsdottir, Thorunn Rafnar, Gudmundur Thorgeirsson, Gisli Masson, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, Kari Stefansson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in NR1H4 (R436H) associating with lower levels of total cholesterol (effect = −0.47 standard deviations or −0.55 mmol L⁻¹, p = 4.21 × 10⁻¹⁰, N = 150,211). Importantly, NR1H4 R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. NR1H4 encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.

Original language	English
Article number	14
Journal	Communications Biology
Volume	1
Issue number	1
DOIs	https://doi.org/10.1038/s42003-018-0015-9
Publication status	Published - 1 Dec 2018

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Publisher Copyright:
© 2018, The Author(s).

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Deaton, A. M., Sulem, P., Nioi, P., Benonisdottir, S., Ward, L. D., Davidsson, O. B., Lao, S., Helgadottir, A., Fan, F., Jensson, B. O., Norddahl, G. L., Jonasdottir, A., Jonasdottir, A., Sigurdsson, A., Kristjansson, R. P., Oddsson, A., Arnadottir, G. A., Jonsson, H., Olafsson, I., ... Stefansson, K. (2018). A rare missense variant in NR1H4 associates with lower cholesterol levels. Communications Biology, 1(1), [14]. https://doi.org/10.1038/s42003-018-0015-9

@article{4eb178f4ff7b4248a242e704c9a56c84,

title = "A rare missense variant in NR1H4 associates with lower cholesterol levels",

abstract = "Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in NR1H4 (R436H) associating with lower levels of total cholesterol (effect = −0.47 standard deviations or −0.55 mmol L−1, p = 4.21 × 10−10, N = 150,211). Importantly, NR1H4 R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. NR1H4 encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.",

author = "Deaton, {Aimee M.} and Patrick Sulem and Paul Nioi and Stefania Benonisdottir and Ward, {Lucas D.} and Davidsson, {Olafur B.} and Socheata Lao and Anna Helgadottir and Fan Fan and Jensson, {Brynjar O.} and Norddahl, {Gudmundur L.} and Aslaug Jonasdottir and Adalbjorg Jonasdottir and Asgeir Sigurdsson and Kristjansson, {Ragnar P.} and Asmundur Oddsson and Arnadottir, {Gudny A.} and Hakon Jonsson and Isleifur Olafsson and Eyjolfsson, {Gudmundur I.} and Olof Sigurdardottir and Bjornsson, {Einar S.} and Sigurdur Olafsson and Thora Steingrimsdottir and Thorunn Rafnar and Gudmundur Thorgeirsson and Gisli Masson and Gudmar Thorleifsson and Gudbjartsson, {Daniel F.} and Hilma Holm and Unnur Thorsteinsdottir and Kari Stefansson",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s42003-018-0015-9",

language = "English",

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Deaton, AM, Sulem, P, Nioi, P, Benonisdottir, S, Ward, LD, Davidsson, OB, Lao, S, Helgadottir, A, Fan, F, Jensson, BO, Norddahl, GL, Jonasdottir, A, Jonasdottir, A, Sigurdsson, A, Kristjansson, RP, Oddsson, A, Arnadottir, GA, Jonsson, H, Olafsson, I, Eyjolfsson, GI, Sigurdardottir, O, Bjornsson, ES, Olafsson, S, Steingrimsdottir, T, Rafnar, T, Thorgeirsson, G, Masson, G, Thorleifsson, G, Gudbjartsson, DF, Holm, H, Thorsteinsdottir, U & Stefansson, K 2018, 'A rare missense variant in NR1H4 associates with lower cholesterol levels', Communications Biology, vol. 1, no. 1, 14. https://doi.org/10.1038/s42003-018-0015-9

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T1 - A rare missense variant in NR1H4 associates with lower cholesterol levels

AU - Deaton, Aimee M.

AU - Sulem, Patrick

AU - Nioi, Paul

AU - Benonisdottir, Stefania

AU - Ward, Lucas D.

AU - Davidsson, Olafur B.

AU - Lao, Socheata

AU - Helgadottir, Anna

AU - Fan, Fan

AU - Jensson, Brynjar O.

AU - Norddahl, Gudmundur L.

AU - Jonasdottir, Aslaug

AU - Jonasdottir, Adalbjorg

AU - Sigurdsson, Asgeir

AU - Kristjansson, Ragnar P.

AU - Oddsson, Asmundur

AU - Arnadottir, Gudny A.

AU - Jonsson, Hakon

AU - Olafsson, Isleifur

AU - Eyjolfsson, Gudmundur I.

AU - Sigurdardottir, Olof

AU - Bjornsson, Einar S.

AU - Olafsson, Sigurdur

AU - Steingrimsdottir, Thora

AU - Rafnar, Thorunn

AU - Thorgeirsson, Gudmundur

AU - Masson, Gisli

AU - Thorleifsson, Gudmar

AU - Gudbjartsson, Daniel F.

AU - Holm, Hilma

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in NR1H4 (R436H) associating with lower levels of total cholesterol (effect = −0.47 standard deviations or −0.55 mmol L−1, p = 4.21 × 10−10, N = 150,211). Importantly, NR1H4 R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. NR1H4 encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.

AB - Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in NR1H4 (R436H) associating with lower levels of total cholesterol (effect = −0.47 standard deviations or −0.55 mmol L−1, p = 4.21 × 10−10, N = 150,211). Importantly, NR1H4 R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. NR1H4 encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.

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U2 - 10.1038/s42003-018-0015-9

DO - 10.1038/s42003-018-0015-9

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AN - SCOPUS:85071044504

SN - 2399-3642

VL - 1

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JF - Communications Biology

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ER -

A rare missense variant in NR1H4 associates with lower cholesterol levels

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