Article | Published:

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

Additional information

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

References

  1. 1.

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

  2. 2.

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

  3. 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).

  4. 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).

  5. 5.

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

  6. 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. 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).

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 12.

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

  13. 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).

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 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).

  18. 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).

  19. 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).

  20. 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).

  21. 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).

  22. 22.

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

  23. 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).

  24. 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).

  25. 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).

  26. 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).

  27. 27.

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

  28. 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).

  29. 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).

  30. 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).

  31. 31.

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

  32. 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).

  33. 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).

  34. 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).

  35. 35.

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

  36. 36.

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

  37. 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).

  38. 38.

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

  39. 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).

  40. 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).

  41. 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).

  42. 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).

  43. 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).

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

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

  48. 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).

  49. 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).

  50. 50.

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

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

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.

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.

Correspondence to Patrick Sulem or Kari Stefansson.

Integrated supplementary information

  1. 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.

  2. 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

  1. Supplementary Text and Figures

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

  2. Reporting Summary

  3. Supplementary Data 1–6

    Supplementary Data 1–6

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

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