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Nat Genet. 2019 Feb;51(2):267-276. doi: 10.1038/s41588-018-0314-6. Epub 2019 Jan 14.

A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.

Author information

1
deCODE genetics/Amgen Inc., Reykjavik, Iceland.
2
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
3
School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
4
Department of Clinical Biochemistry, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
5
The Laboratory in Mjodd, RAM, Reykjavik, Iceland.
6
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
7
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
8
Department of Laboratory Hematology, Landspítali, the National University Hospital of Iceland, Reykjavik, Iceland.
9
Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
10
Department of Sleep, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
11
Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
12
Department of Respiratory Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
13
The Medical Center Mjodd, Reykjavik, Iceland.
14
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
15
deCODE genetics/Amgen Inc., Reykjavik, Iceland. patrick.sulem@decode.is.
16
deCODE genetics/Amgen Inc., Reykjavik, Iceland. kari.stefansson@decode.is.
17
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. kari.stefansson@decode.is.

Abstract

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.

PMID:
30643255
DOI:
10.1038/s41588-018-0314-6
[Indexed for MEDLINE]

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