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

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.

Fig. 1: Manhattan plot for the combined nasal polyp GWAS (Iceland, n = 1,175 cases and 309,305 controls; UK, n= 3,191 cases and 405,376 controls).
Fig. 2: Manhattan plot for the combined chronic rhinosinusitis GWAS (Iceland, n = 3,188 cases and 353,939 controls; UK, n = 2,420 cases and 406,147 controls).
Fig. 3: Reported eosinophil count variants and risk of nasal polyps.
Fig. 4: Scatter plot showing 34 previously reported asthma SNPs.
Fig. 5: Reported allergy variants and risk of nasal polyps.

Data availability

The Icelandic population whole-genome sequencing data have been deposited in the European Variant Archive under accession code PRJEB15197. The authors declare that the data supporting the findings of this study are available within the article, in its Supplementary Data files, and upon reasonable request.

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Acknowledgements

We thank the individuals who participated in this study and whose contribution made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This study was supported in part by the National Institute of Dental and Craniofacial Research of the National Institutes of Health, under award number R01DE022905. This research has been conducted using the UK Biobank Resource under application number 24711.

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R.P.K., S.B., O.B.D., G.S., D.F.G., U.T., T.R., P.S., and K.S. designed the study and interpreted the results. R.P.K., S.B., O.B.D., A.O., V.T., I.O., G.I.E., O.S., P.T.O., D.G., T.G., B.R.L., D.L., T.A.O., F.Z., G.B., U.S.B., G.T., I.J., and P.S. carried out the subject ascertainment and recruitment. R.P.K., S.J., B.V.H., B.G., G.H.H., O.A.S., G.M., O.T.M., G.L.N., and P.S. performed the sequencing, genotyping, and expression analyses. R.P.K., S.B., O.B.D., J.K.S., L.S., J.G.A., B.O.J., G.A.A., A.O., G.R.O., A.M.D., D.F.G., and P.S. performed the statistical and bioinformatics analyses. R.P.K., D.F.G., U.T., G.L.N., I.J., P.S., and K.S. drafted the manuscript. All authors contributed to the final version of the paper.

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Correspondence to Patrick Sulem or Kari Stefansson.

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Authors affiliated with deCODE genetics/Amgen Inc. declare competing interests as employees. The remaining authors declare no competing interests. A.M.D. is a shareholder of Amgen Inc.

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Integrated supplementary information

Supplementary Figure 1 Locus plots for the Icelandic data showing the associations of variants (discovered by whole-genome sequencing of 15,220 Icelanders) at the ALOX15 locus with nasal polyps (n = 1,175).

The leading variant is shown as a purple diamond, and other variants are colored according to correlation (r2) with the leading marker (legend at top-left). –log10P values are shown along the left y-axis (two-sided logistic regression), and correspond to the variants depicted in the plot. The right y-axis shows calculated recombination rates at the chromosomal location, plotted as a solid blue line.

Supplementary Figure 2 Box plots depicting the effects of Thr560Met on eosinophil count in Iceland.

The plot on the left shows the genotypic effect for all chip-typed individuals in the Icelandic dataset with eosinophil count measured (n = 128,971). The right plot shows the effect when the eosinophil sample is stratified by nasal polyp status (n = 1,086 cases and 217,856 controls). The median is depicted as a horizontal black line, the interquartile range (IQR) is depicted by the upper and lower bounds of the rectangle, and data within 1.5 IQR of the boxes are depicted by the whiskers. Data falling outside this range are depicted as hollow circles.

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Kristjansson, R.P., Benonisdottir, S., Davidsson, O.B. et al. A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis. Nat Genet 51, 267–276 (2019). https://doi.org/10.1038/s41588-018-0314-6

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