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

• Published in: Nature genetics Vol. 51; no. 2; pp. 267 - 276
• Main Authors: Kristjansson, Ragnar P., Benonisdottir, Stefania, Davidsson, Olafur B., Oddsson, Asmundur, Tragante, Vinicius, Sigurdsson, Jon K., Stefansdottir, Lilja, Jonsson, Stefan, Jensson, Brynjar O., Arthur, Joseph G., Arnadottir, Gudny A., Sulem, Gerald, Halldorsson, Bjarni V., Gunnarsson, Bjarni, Halldorsson, Gisli H., Stefansson, Olafur A., Oskarsson, Gudjon R., Deaton, Aimee M., Olafsson, Isleifur, Eyjolfsson, Gudmundur I., Sigurdardottir, Olof, Onundarson, Pall T., Gislason, David, Gislason, Thorarinn, Ludviksson, Bjorn R., Ludviksdottir, Dora, Olafsdottir, Thorunn A., Rafnar, Thorunn, Masson, Gisli, Zink, Florian, Bjornsdottir, Gyda, Magnusson, Olafur Th, Bjornsdottir, Unnur S., Thorleifsson, Gudmar, Norddahl, Gudmundur L., Gudbjartsson, Daniel F., Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, Sulem, Patrick, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2019; Nature Publishing Group
• Subjects: 38/39; 45/23; 45/43; 45/91; 631/208/205/2138; 692/699/1785; 692/699/249/2510; Adult; Agriculture; Animal Genetics and Genomics; Arachidonate 15-lipoxygenase; Arachidonate 15-Lipoxygenase - genetics; Asthma; Asthma - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chronic Disease; Complications and side effects; Confidence intervals; Consortia; Disease; Enzymatic activity; Enzymes; Eosinophils - pathology; Europeans; Female; Gene expression; Gene Function; Genetic aspects; Genetic variation; Genetic Variation - genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics; Human Genetics; Humans; Iceland; Lesions; Leukocyte Count - methods; Leukocytes (eosinophilic); Lipoxygenase; Male; Markers; Mucosa; Mutation; Nasal polyps; Nasal Polyps - genetics; Nasal Polyps - pathology; Paranasal sinus; Phenotypes; Polyps; Prevention; Rhinitis; Rhinosinusitis; Risk analysis; Risk factors; Sinus; Sinusitis; Sinusitis - genetics; Sinusitis - pathology; Iceland; United Kingdom > UK
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-018-0314-6

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. Genome-wide-association analyses of datasets from Iceland and the UK identify risk variants for nasal polyps and chronic rhinosinusitis. Notably, a loss-of-function missense variant in ALOX15 confers protection against both phenotypes, thus identifying a potential target for therapeutic intervention.