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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.

SUBMITTER: Deaton AM 

PROVIDER: S-EPMC6123719 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A rare missense variant in <i>NR1H4</i> associates with lower cholesterol levels.

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

Communications biology 20180208


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 <i>NR1H4</i> (R436H) associating with lower levels of total cholesterol (effect = -0.47 standard deviations or -0.55 mmol L<sup>-1</sup>, <i>p</i> = 4.21 × 10<sup>-10</sup>, <i>N</i  ...[more]

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