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Commun Biol. 2018 Feb 8;1:14. doi: 10.1038/s42003-018-0015-9. eCollection 2018.

A rare missense variant in NR1H4 associates with lower cholesterol levels.

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, 101 Iceland.
2
2Faculty of Medicine, University of Iceland, Reykjavik, 101 Iceland.
3
3Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, 101 Iceland.
4
Laboratory in Mjódd (RAM), Reykjavik, 109 Iceland.
5
5Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, 600 Iceland.
6
6Department of Medicine, Landspitali University Hospital, Reykjavik, 101 Iceland.
7
7Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, 101 Iceland.
8
8Division of Cardiology, Department of Internal Medicine, Landspitali University Hospital, Reykjavik, 101 Iceland.
9
9School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101 Iceland.

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.

Conflict of interest statement

A.M.D., P.S., P.N, S.B., L.D.W., O.B.D., S.L., A.H., F.F., B.O.J., G.L.N., As.J., Ad.J., A.S., R.P.K., A.O., G.A.A., H.J., T.R., G.Thorg., G.M., G.Thorl., D.F.G., H.H., U.T. and K.S. who are affiliated with deCODE genetics/Amgen declare competing financial interests as employees. The remaining authors declare no competing financial interests.

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