Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Nature Genetics volume 51, pages 267–276 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Newton, J. R. & Ah-See, K. W. A review of nasal polyposis. Ther. Clin. Risk Manag. 4, 507–512 (2008).

    Article  Google Scholar 

  2. Drake-Lee, A. B. Nasal polyps. Hosp. Med. 65, 264–267 (2004).

    Article  CAS  Google Scholar 

  3. Cingi, C., Demirbas, D. & Ural, A. Nasal polyposis: an overview of differential diagnosis and treatment. Recent Pat. Inflamm. Allergy Drug Discov. 5, 241–252 (2011).

    Article  CAS  Google Scholar 

  4. Gliklich, R. E. & Metson, R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol. Head Neck Surg. 113, 104–109 (1995).

    Article  CAS  Google Scholar 

  5. Deal, R. T. & Kountakis, S. E. Significance of nasal polyps in chronic rhinosinusitis: symptoms and surgical outcomes. Laryngoscope 114, 1932–1935 (2004).

    Article  Google Scholar 

  6. Stevens, W. W., Schleimer, R. P., Chandra, R. K. & Peters, A. T. Biology of nasal polyposis. J. Allergy Clin. Immunol. 133, 1503.e1-4 (2014).

  7. Staikūniene, J., Vaitkus, S., Japertiene, L. M. & Ryskiene, S. Association of chronic rhinosinusitis with nasal polyps and asthma: clinical and radiological features, allergy and inflammation markers. Medicina 44, 257–265 (2008).

    Article  Google Scholar 

  8. Fokkens, W. J. et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50, 1–12 (2012).

    Article  Google Scholar 

  9. Gevaert, P. et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J. Allergy Clin. Immunol. 128, 989–995 (2011).

    Article  CAS  Google Scholar 

  10. Alobid, I. et al. Nasal polyposis and its impact on quality of life: comparison between the effects of medical and surgical treatments. Allergy 60, 452–458 (2005).

    Article  CAS  Google Scholar 

  11. Gevaert, P. et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J. Allergy Clin. Immunol. 131, 110–116 (2013).

    Article  CAS  Google Scholar 

  12. Gudbjartsson, D. F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).

    Article  CAS  Google Scholar 

  13. Sveinbjornsson, G. et al. Weighting sequence variants based on their annotation increases power of whole-genome association studies. Nat. Genet. 48, 314–317 (2016).

    Article  CAS  Google Scholar 

  14. Klossek, J. et al. Prevalence of nasal polyposis in France: a cross-sectional, case-control study. Allergy 60, 233–237 (2005).

    Article  CAS  Google Scholar 

  15. Langdon, C. & Mullol, J. Nasal polyps in patients with asthma: prevalence, impact, and management challenges. J. Asthma Allergy 9, 45–53 (2016).

    PubMed  PubMed Central  Google Scholar 

  16. Pickrell, J. K. et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709–717 (2016).

    Article  CAS  Google Scholar 

  17. Demenais, F. et al. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nat. Genet. 50, 42–53 (2018).

    Article  CAS  Google Scholar 

  18. Feltenmark, S. et al. Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells. Proc. Natl Acad. Sci. USA 105, 680–685 (2008).

    Article  CAS  Google Scholar 

  19. Claesson, H.-E. On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma. Prostaglandins Other Lipid Mediat. 89, 120–125 (2009).

    Article  CAS  Google Scholar 

  20. Astle, W. J. et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415–1429 (2016).

    Article  CAS  Google Scholar 

  21. Ferreira, M. A. et al. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat. Genet. 49, 1752–1757 (2017).

    Article  CAS  Google Scholar 

  22. GTEx Portal Version 7, http://www.gtexportal.org (NIH Common Fund, accessed 10 September 2017).

  23. Schurmann, K. et al. Molecular basis for the reduced catalytic activity of the naturally occurring T560M mutant of human 12/15-lipoxygenase that has been implicated in coronary artery disease. J. Biol. Chem. 286, 23920–23927 (2011).

    Article  CAS  Google Scholar 

  24. Assimes, T. L. et al. A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease. Atherosclerosis 198, 136–144 (2008).

    Article  CAS  Google Scholar 

  25. Chang, J. et al. 12/15 lipoxygenase regulation of colorectal tumorigenesis is determined by the relative tumor levels of its metabolite 12-HETE and 13-HODE in animal models. Oncotarget 6, 2879–2888 (2015).

    PubMed  Google Scholar 

  26. Smith, D. et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. PLoS Genet. 13, e1006659 (2017).

    Article  Google Scholar 

  27. Mousas, A. et al. Rare coding variants pinpoint genes that control human hematological traits. PLoS Genet. 13, e1006925 (2017).

    Article  Google Scholar 

  28. Paternoster, L. et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat. Genet. 47, 1449–1456 (2015).

    Article  Google Scholar 

  29. Baurecht, H. et al. Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am. J. Hum. Genet. 96, 104–120 (2015).

    Article  CAS  Google Scholar 

  30. Kelavkar, U. P. & Badr, K. F. Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene. Proc. Natl Acad. Sci. USA 96, 4378–4383 (1999).

    Article  CAS  Google Scholar 

  31. Rostkowska-Nadolska, B. et al. A microarray study of gene expression profiles in nasal polyps. Auris Nasus Larynx 38, 58–64 (2011).

    Article  Google Scholar 

  32. Andersson, C. K. et al. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling. Am. J. Respir. Cell Mol. Biol. 39, 648–656 (2008).

    Article  CAS  Google Scholar 

  33. Brunnström, Å. et al. On the biosynthesis of 15-HETE and eoxin C4 by human airway epithelial cells. Prostaglandins Other Lipid Mediat. 121, 83–90 (2015).

    Article  Google Scholar 

  34. James, A. et al. The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma. Int. Arch. Allergy Immunol. 162, 135–142 (2013).

    Article  CAS  Google Scholar 

  35. Steinke, J. W. & Culp, J. A. Leukotriene synthesis inhibitors versus antagonists: the pros and cons. Curr. Allergy Asthma. Rep. 7, 126–133 (2007).

    Article  CAS  Google Scholar 

  36. Sadeghian, H. & Jabbari, A. 15-Lipoxygenase inhibitors: a patent review. Expert Opin. Ther. Pat. 26, 65–88 (2016).

    Article  CAS  Google Scholar 

  37. Jaworski, K., Jankowski, P. & Kosior, D. A. PCSK9 inhibitors—from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade. Arch. Med. Sci. 13, 914–929 (2017).

    Article  CAS  Google Scholar 

  38. Jónsson, H. et al. Whole genome characterization of sequence diversity of 15,220 Icelanders. Sci. Data 4, 170115 (2017).

    Article  Google Scholar 

  39. Gulcher, J. R., Kristjánsson, K., Gudbjartsson, H. & Stefánsson, K. Protection of privacy by third-party encryption in genetic research in Iceland. Eur. J. Hum. Genet. 8, 739–742 (2000).

    Article  CAS  Google Scholar 

  40. Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

    Article  CAS  Google Scholar 

  41. Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).

    Article  Google Scholar 

  42. Wain, L. V. et al. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir. Med. 3, 769–781 (2015).

    Article  Google Scholar 

  43. Welsh, S., Peakman, T., Sheard, S. & Almond, R. Comparison of DNA quantification methodology used in the DNA extraction protocol for the UK Biobank cohort. BMC Genomics 18, 26 (2017).

    Article  Google Scholar 

  44. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article  Google Scholar 

  45. UK10K Consortium. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

    Article  Google Scholar 

  46. McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

    Article  CAS  Google Scholar 

  47. Bycroft, C. et al. The UK Biobank Resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    Article  CAS  Google Scholar 

  48. Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl Cancer Inst. 22, 719–748 (1959).

    CAS  PubMed  Google Scholar 

  49. Oskarsson, G. R. et al. A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin. Commun. Biol. 1, 49 (2018).

    Article  Google Scholar 

  50. Kehr, B. et al. Diversity in non-repetitive human sequences not found in the reference genome. Nat. Genet. 49, 588–593 (2017).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. deCODE genetics/Amgen Inc., Reykjavik, Iceland

    Ragnar P. Kristjansson, Stefania Benonisdottir, Olafur B. Davidsson, Asmundur Oddsson, Vinicius Tragante, Jon K. Sigurdsson, Lilja Stefansdottir, Stefan Jonsson, Brynjar O. Jensson, Joseph G. Arthur, Gudny A. Arnadottir, Gerald Sulem, Bjarni V. Halldorsson, Bjarni Gunnarsson, Gisli H. Halldorsson, Olafur A. Stefansson, Gudjon R. Oskarsson, Aimee M. Deaton, Thorunn A. Olafsdottir, Thorunn Rafnar, Gisli Masson, Florian Zink, Gyda Bjornsdottir, Olafur Th. Magnusson, Gudmar Thorleifsson, Gudmundur L. Norddahl, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Patrick Sulem & Kari Stefansson

  2. Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands

    Vinicius Tragante

  3. School of Science and Engineering, Reykjavik University, Reykjavik, Iceland

    Bjarni V. Halldorsson

  4. Department of Clinical Biochemistry, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Isleifur Olafsson

  5. The Laboratory in Mjodd, RAM, Reykjavik, Iceland

    Gudmundur I. Eyjolfsson

  6. Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland

    Olof Sigurdardottir

  7. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland

    Pall T. Onundarson, David Gislason, Thorarinn Gislason, Bjorn R. Ludviksson, Dora Ludviksdottir, Thorunn A. Olafsdottir, Unnur Thorsteinsdottir, Ingileif Jonsdottir & Kari Stefansson

  8. Department of Laboratory Hematology, Landspítali, the National University Hospital of Iceland, Reykjavik, Iceland

    Pall T. Onundarson

  9. Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    David Gislason & Unnur S. Bjornsdottir

  10. Department of Sleep, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Thorarinn Gislason

  11. Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Bjorn R. Ludviksson

  12. Department of Respiratory Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Dora Ludviksdottir

  13. The Medical Center Mjodd, Reykjavik, Iceland

    Unnur S. Bjornsdottir

  14. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Daniel F. Gudbjartsson

Authors
  1. Ragnar P. Kristjansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefania Benonisdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olafur B. Davidsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asmundur Oddsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vinicius Tragante
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jon K. Sigurdsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lilja Stefansdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stefan Jonsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Brynjar O. Jensson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joseph G. Arthur
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gudny A. Arnadottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gerald Sulem
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bjarni V. Halldorsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Bjarni Gunnarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gisli H. Halldorsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Olafur A. Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Gudjon R. Oskarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Aimee M. Deaton
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Isleifur Olafsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Gudmundur I. Eyjolfsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Olof Sigurdardottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Pall T. Onundarson
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. David Gislason
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Thorarinn Gislason
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Bjorn R. Ludviksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Dora Ludviksdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Thorunn A. Olafsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Thorunn Rafnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Gisli Masson
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Florian Zink
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Gyda Bjornsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Olafur Th. Magnusson
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Unnur S. Bjornsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Gudmar Thorleifsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Gudmundur L. Norddahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Daniel F. Gudbjartsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Unnur Thorsteinsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Ingileif Jonsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Patrick Sulem
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Kari Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

Ethics declarations

Competing interests

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Note and Supplementary Tables 1–22

Reporting Summary

Supplementary Data 1–6

Supplementary Data 1–6

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41588-018-0314-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing