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.

  • Original Article
  • Published:

The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene–environment interaction

Genes & Immunity volume 18, pages 75–81 (2017)Cite this article

Subjects

Abstract

The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA− along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene–environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Poli F, Pizza F, Mignot E, Ferri R, Pagotto U, Taheri S et al. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 2013; 36: 175–181.

    Article  Google Scholar 

  2. Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O . Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014; 13: 600–613.

    Article  CAS  Google Scholar 

  3. Scammell TE . Narcolepsy. N Engl J Med 2015; 373: 2654–2662.

    Article  CAS  Google Scholar 

  4. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E . Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39–40.

    Article  CAS  Google Scholar 

  5. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002; 59: 1553–1562.

    Article  Google Scholar 

  6. Mignot E . Genetic and familial aspects of narcolepsy. Neurology 1998; 50 (Suppl 1): S16–S22.

    Article  CAS  Google Scholar 

  7. Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol 2011; 70: 410–417.

    Article  Google Scholar 

  8. Picchioni D, Hope CR, Harsh JR . A case–control study of the environmental risk factors for narcolepsy. Neuroepidemiology 2007; 29: 185–192.

    Article  Google Scholar 

  9. Ambati A, Poiret T, Svahn BM, Valentini D, Khademi M, Kockum I et al Increased Beta-Haemolytic Group. A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. J Intern Med 2015; 278: 264–276.

    Article  CAS  Google Scholar 

  10. Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 2009; 32: 979–983.

    Article  Google Scholar 

  11. Han F, Lin L, Li J, Dong SX, An P, Zhao L et al. HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens 2012; 80: 328–335.

    Article  CAS  Google Scholar 

  12. Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CE et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet 2010; 42: 786–789.

    Article  CAS  Google Scholar 

  13. Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 2014; 37: 19–25.

    Article  Google Scholar 

  14. Miyagawa T, Toyoda H, Hirataka A, Kanbayashi T, Imanishi A, Sagawa Y et al. New susceptibility variants to narcolepsy identified in HLA class II region. Hum Mol Genet 2015; 24: 891–898.

    Article  CAS  Google Scholar 

  15. Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001; 68: 686–699.

    Article  CAS  Google Scholar 

  16. Ollila HM, Ravel JM, Han F, Faraco J, Lin L, Zheng X et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 2015; 96: 136–146.

    Article  CAS  Google Scholar 

  17. Tafti M, Lammers GJ, Dauvilliers Y, Overeem S, Mayer G, Nowak J et al. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep 2016; 39: 581–587.

    Article  Google Scholar 

  18. Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet 2009; 41: 708–711.

    Article  CAS  Google Scholar 

  19. Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet 2011; 43: 66–71.

    Article  CAS  Google Scholar 

  20. Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet 2013; 9: e1003270.

    Article  CAS  Google Scholar 

  21. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, Hublin C, Linna M, Olsen P et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One 2012; 7: e33723.

    Article  CAS  Google Scholar 

  22. Szakacs A, Darin N, Hallbook T . Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 2013; 80: 1315–1321.

    Article  Google Scholar 

  23. Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N . Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. J Intern Med 2014; 275: 172–190.

    Article  CAS  Google Scholar 

  24. Verstraeten T, Cohet C, Dos Santos G, Ferreira GL, Bollaerts K, Bauchau V et al. Pandemrix and narcolepsy: a critical appraisal of the observational studies. Hum Vaccin Immunother 2016; 12: 187–193.

    Article  Google Scholar 

  25. Han F, Lin L, Li J, Dong XS, Mignot E . Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann Neurol 2013; 73: 560.

    Article  Google Scholar 

  26. Harkiolaki M, Holmes SL, Svendsen P, Gregersen JW, Jensen LT, McMahon R et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity 2009; 30: 348–357.

    Article  CAS  Google Scholar 

  27. Vaarala O, Vuorela A, Partinen M, Baumann M, Freitag TL, Meri S et al. Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk. PLoS One 2014; 9: e114361.

    Article  Google Scholar 

  28. Ahmed SS, Schur PH, MacDonald NE, Steinman L . Narcolepsy, 2009 A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants. J Autoimmun 2014; 50: 1–11.

    Article  CAS  Google Scholar 

  29. Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med 2015; 7: 294ra105.

    Article  Google Scholar 

  30. Fearnley JM, Lees AJ . Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991; 114: 2283–2301.

    Article  Google Scholar 

  31. Hedstrom AK, Olsson T, Alfredsson L . High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler 2012; 18: 1334–1336.

    Article  Google Scholar 

  32. Hedstrom AK, Sundqvist E, Baarnhielm M, Nordin N, Hillert J, Kockum I et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 2011; 134 (Part 3): 653–664.

    Article  Google Scholar 

  33. Sundqvist E, Sundstrom P, Linden M, Hedstrom AK, Aloisi F, Hillert J et al. Epstein–Barr virus and multiple sclerosis: interaction with HLA. Genes Immun 2012; 13: 14–20.

    Article  CAS  Google Scholar 

  34. European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic influenza vaccination. A multi-country European epidemiological investigation. ECDC Technical report, 2012. http://ecdc.europa.eu/en/publications/Publications/Vaesco%20report%20FINAL%20with%20cover.pdf (accessed on 1 October 2016).

  35. Lamb F, Ploner A, Fink K, Maeurer M, Bergman P, Piehl F et al. No evidence for disease history as a risk factor for narcolepsy after A(H1N1)pdm09 vaccination. PLoS One 2016; 11: e0154296.

    Article  Google Scholar 

  36. Poli F, Overeem S, Lammers GJ, Plazzi G, Lecendreux M, Bassetti CL et al. Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Vaccine 2013; 31: 994–1007.

    Article  Google Scholar 

  37. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L . Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009; 73: 696–701.

    Article  Google Scholar 

  38. Chernogubova E, Strawbridge R, Mahdessian H, Malarstig A, Krapivner S, Gigante B et al. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscler Thromb Vasc Biol 2012; 32: 1526–1534.

    Article  CAS  Google Scholar 

  39. Li J, Humphreys K, Heikkinen T, Aittomaki K, Blomqvist C, Pharoah PD et al. A combined analysis of genome-wide association studies in breast cancer. Breast Cancer Res Treat 2011; 126: 717–727.

    Article  CAS  Google Scholar 

  40. Magnusson C, Baron J, Persson I, Wolk A, Bergstrom R, Trichopoulos D et al. Body size in different periods of life and breast cancer risk in post-menopausal women. Int J Cancer 1998; 76: 29–34.

    Article  CAS  Google Scholar 

  41. Rosenberg LU, Einarsdottir K, Friman EI, Wedren S, Dickman PW, Hall P et al. Risk factors for hormone receptor-defined breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2006; 15: 2482–2488.

    Article  CAS  Google Scholar 

  42. EIMS-Studien. Epidemiological Investigation of Multiple Sclerosis. Karolinska Institutet: Stockholm, Sweden. http://www.eims.nu/NeurologyDepartments.htm (accessed on 1 October 2016).

  43. Broadbent HM, Peden JF, Lorkowski S, Goel A, Ongen H, Green F et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet 2008; 17: 806–814.

    Article  CAS  Google Scholar 

  44. Dilthey AT, Moutsianas L, Leslie S, McVean G . HLA*IMP—an integrated framework for imputing classical HLA alleles from SNP genotypes. Bioinformatics 2011; 27: 968–972.

    Article  CAS  Google Scholar 

  45. Lindgren BW . The Bernoulli Model. In: Statistical Theory. Collier Macmillan Publishers: London, UK, 1976, p 29.

  46. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ . Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 2015; 4: 7.

    Article  Google Scholar 

  47. Purcell S, Cherny SS, Sham PC . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Jesse Huang (Karolinska Institutet, Stockholm, Sweden) for his assistance with manuscript preparation. This study primarily received grant support from the Swedish Medical Products Agency (MPA). The genotypes of the large control material have received support from the Swedish research council, Knut and Alice Wallenberg foundation, the AFA foundation and Swedish Brain Foundation. Case and control identification was funded by the European Center of Disease Control (VAESCO) and MPA. MPA also funded the collection of blood samples.

Disclaimer

This manuscript represents the views of the authors, not necessarily those of the Swedish Medical Products Agency, where one of the authors (NF) was employed at the time of the study.

Author information

Authors and Affiliations

  1. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    I L Bomfim, K Fink, L Franzén, V Azhary, I Kockum & T Olsson

  2. Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden

    I L Bomfim, A Silveira, L Franzén, V Azhary, I Kockum & T Olsson

  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    F Lamb & L Arnheim-Dahlström

  4. Department of Neurology, Karolinska University Hospital, Stockholm, Sweden

    K Fink & T Olsson

  5. Department of Pediatrics, Halmstad County Hospital, Halmstad, Sweden

    A Szakács

  6. Department of Medicine, Cardiovascular Medicine Unit, Karolinska Institutet, Solna, Sweden

    A Silveira

  7. Division of Therapeutic Immunology, Department of Laboratory Medicine, Stockholm, Sweden

    M Maeurer

  8. Center for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden

    M Maeurer

  9. Medical Products Agency, Uppsala, Sweden

    N Feltelius

  10. Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

    N Darin & T Hallböök

Authors
  1. I L Bomfim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Lamb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Szakács
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Silveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Franzén
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V Azhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Maeurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N Feltelius
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N Darin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T Hallböök
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L Arnheim-Dahlström
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. I Kockum
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T Olsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I L Bomfim.

Ethics declarations

Competing interests

LAD has obtained funding from MDS Sanofi Pasteur and from GlaxoSmithKline for other studies than this one. TO has received unrestricted multiple sclerosis research grants from Biogen, AstraZeneca, Novartis and Genzyme. IK has received unrestricted multiple sclerosis research grants from AstraZeneca. The other authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bomfim, I., Lamb, F., Fink, K. et al. The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene–environment interaction. Genes Immun 18, 75–81 (2017). https://doi.org/10.1038/gene.2017.1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2017.1

This article is cited by

Search

Advanced search

Quick links