Artigo Acesso aberto Revisado por pares

A rare missense variant in NR1H4 associates with lower cholesterol levels

2018; Nature Portfolio; Volume: 1; Issue: 1 Linguagem: Inglês

10.1038/s42003-018-0015-9

ISSN

2399-3642

Autores

Aimée M. Deaton, Patrick Sulem, Paul Nioi, Stefania Benónísdóttir, Lucas D. Ward, Olafur B. Davidsson, Socheata Lao, Anna Helgadóttir, Fan Fan, Brynjar Ö. Jensson, Gudmundur L. Norddahl, Áslaug Jónasdóttir, Aðalbjörg Jónasdóttir, Ásgeir Sigurðsson, Ragnar P. Kristjansson, Ásmundur Oddsson, Gudny A. Arnadottir, Hákon Jónsson, Ísleifur Ólafsson, Guðmundur I. Eyjólfsson, Ólöf Sigurðardóttir, Einar S. Björnsson, Sigurður Ólafsson, Þóra Steingrímsdóttir, Þórunn Rafnar, Guðmundur Þorgeirsson, Gísli Másson, Guðmar Þorleifsson, Daníel F. Guðbjartsson, Hilma Hólm, Unnur Þorsteinsdóttir, Kári Stéfansson,

Tópico(s)

Metabolism and Genetic Disorders

Resumo

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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