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:

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

Genes & Immunity volume 13, pages 59–65 (2012)Cite this article

Abstract

TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) mutations seem to be associated with autoimmunity and common variable immunodeficiency in humans. Because of its role in immune responses, we investigated the association between TACI mutations and infection proneness/asthma symptoms in children. A total of 2372 children were genotyped for TACI mutations (I87N, C104R, S144X, A181E, R202H and ins204A). Serum IgA, IgG and specific IgE levels were determined in children with mutations. Data on parentally reported allergic diseases and infections were collected. In all, 55 individuals with TACI mutations were identified. Children with TACI mutations had a 2-fold increased risk of wheeze at 2 and 4 years of age and a 2.5-fold increased risk of asthma was seen at 4 years of age. None of the children with mutations suffered from IgA deficiency (<0.07 g l−1). No significant differences in serum IgG levels or specific IgE were found. Common variants in asthma susceptibility genes may account for up to 40% of cases of childhood-onset asthma, indicating a high contribution, compared with other common disorders. The role of rare variants/mutations in the pathogenesis of asthma is less clear. We conclude that mutations in TACI are the contributing factors for asthma symptoms in Swedish children, although the mechanisms still remain elusive.

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
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.

    Article  CAS  PubMed  Google Scholar 

  2. Pritchard JK . Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001; 69: 124–137.

    Article  CAS  PubMed  Google Scholar 

  3. van den Oord RAHM, Sheikh A . Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ 2009; 339: b2433.

    Article  PubMed  Google Scholar 

  4. Haller G, Torgerson DG, Ober C, Thompson EE . Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility. J Allergy Clin Immunol 2009; 124: 1204–1209.e9.

    Article  CAS  PubMed  Google Scholar 

  5. Chang SK, Arendt BK, Darce JR, Wu X, Jelinek DF . A role for BLyS in the activation of innate immune cells. Blood 2006; 108: 2687–2694.

    Article  CAS  PubMed  Google Scholar 

  6. Mackay F, Schneider P, Rennert P, Browning J . BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol 2003; 21: 231–264.

    Article  CAS  PubMed  Google Scholar 

  7. Ng LG, Mackay CR, Mackay F . The BAFF/APRIL system: life beyond B lymphocytes. Mol Immunol 2005; 42: 763–772.

    Article  CAS  PubMed  Google Scholar 

  8. Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med 2005; 201: 35–39.

    Article  CAS  PubMed  Google Scholar 

  9. Xu S, Lam KP . B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. Mol Cell Biol 2001; 21: 4067–4074.

    Article  CAS  PubMed  Google Scholar 

  10. Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol 2001; 2: 638–643.

    Article  CAS  PubMed  Google Scholar 

  11. Mantchev GT, Cortesão CS, Rebrovich M, Cascalho M, Bram RJ . TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens. J Immunol 2007; 179: 2282–2288.

    Article  CAS  PubMed  Google Scholar 

  12. Seshasayee D, Valdez P, Yan M, Dixit VM, Tumas D, Grewal IS . Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity 2003; 18: 279–288.

    Article  CAS  PubMed  Google Scholar 

  13. Salzer U, Chapel HM, Webster AD, Pan-Hammarström Q, Schmitt-Graeff A, Schlesier M et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005; 37: 820–828.

    Article  CAS  PubMed  Google Scholar 

  14. Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005; 37: 829–834.

    Article  CAS  PubMed  Google Scholar 

  15. Pan-Hammarström Q, Salzer U, Du L, Björkander L, Cunningham-Rundles C, Nelson DL et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 2007; 39: 429–430.

    Article  PubMed  Google Scholar 

  16. Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol 1997; 109 (Suppl 1): 1–28.

  17. Salzer U, Bacchelli C, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 2009; 113: 1967–1976.

    Article  CAS  PubMed  Google Scholar 

  18. Inoue K, Minerharu Y, Inoue S, Yamada S, Matsuda F, Nozaki K et al. Search on chromosome 17 centromere reveals TNFRSF13B as a susceptibility gene for intracranial aneurysm: a preliminary study. Circulation 2006; 113: 2002–2010.

    Article  PubMed  Google Scholar 

  19. Martínez-Pomar N, Detková D, Arostegui JI, Alvarez A, Soler-Palacín P, Vidaller A et al. Role of TNFRSF13B variants in patients with common variable immunodeficiency. Blood 2009; 114: 2846–2848.

    Article  PubMed  Google Scholar 

  20. Garibyan L, Lobito AA, Siegel RM, Call ME, Wucherpfennig KW, Geha RS . Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID). J Clin Invest 2007; 117: 1550–1557.

    Article  CAS  PubMed  Google Scholar 

  21. Lee JJ, Rauter I, Garibyan L, Ozcan E, Sannikova T, Dillon SR et al. The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood 2009; 114: 2254–2262.

    Article  CAS  PubMed  Google Scholar 

  22. Fried AJ, Rauter I, Dillon SR, Jabara HH, Geha RS . Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J Allergy Clin Immunol 2011; 128: 226–228.

    Article  CAS  PubMed  Google Scholar 

  23. Hymowitz SG, Patel DR, Wallweber HJ, Runyon S, Yan M, Yin J et al. Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding. J Biol Chem 2005; 280: 7218–7227.

    Article  CAS  PubMed  Google Scholar 

  24. Ingold K, Zumsteg A, Tardivel A, Huard B, Steiner QG, Cachero CG et al. Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med 2005; 201: 1375–1383.

    Article  CAS  PubMed  Google Scholar 

  25. Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F et al. Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol 2003; 23: 1428–1440.

    Article  CAS  PubMed  Google Scholar 

  26. Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med 2000; 192: 137–143.

    Article  CAS  PubMed  Google Scholar 

  27. Melén E, Neiberg F, Lindgren CM, Berglind N, Zuchelli M, Nordling E et al. Interactions between glutathione S-transferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic disease. Environ Health Perspect 2008; 116: 1077–1084.

    Article  PubMed  Google Scholar 

  28. Moffatt MF, Gut IG, Demenais M, Strachan DP, Bouzigon E, Heath S et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010; 363: 1211–1221.

    Article  CAS  PubMed  Google Scholar 

  29. Janzi M, Kull I, Sjöberg R, Wan J, Melén E, Bayat N et al. Selective IgA deficiency in early life: association to infections and allergic diseases during childhood. Clin Immunol 2009; 133: 78–85.

    Article  CAS  Google Scholar 

  30. Ostblom E, Lilja G, Pershagen G, van Hage M, Wickman M . Phenotypes of food hypersensitivity and development of allergic diseases during the first 8 years of life. Clin Exp Allergy 2008; 38: 1325–1332.

    Article  CAS  PubMed  Google Scholar 

  31. Ostblom E, Egmar A-C, Gardulf A, Lilja G, Wickman M . The impact of food hypersensitivity reported in 9-year-old children by their parents on health-related quality of life. Allergy 2008; 63: 211–218.

    Article  CAS  PubMed  Google Scholar 

  32. Ostblom E, Lilja G, Ahlstedt S, van Hage M, Wickman M . Patterns of quantitative food-specific IgE-antibodies and reported food hypersensitivity in 4-year-old children. Allergy 2008; 63: 418–424.

    Article  CAS  PubMed  Google Scholar 

  33. Ostblom E, Wickman M, van Hage M, Lilja G . Reported symptoms of food hypersensitivity and sensitization to common foods in 4-year-old children. Acta Paediatr 2008; 97: 85–90.

    Article  PubMed  Google Scholar 

  34. Kull I, Melen E, Alm J, Hallberg J, Svartengren M, van Hage M et al. Breast-feeding in relation to asthma, lung function, and sensitization in young schoolchildren. J Allergy Clin Immunol 2010; 125: 1013–1019.

    Article  PubMed  Google Scholar 

  35. Mohammadi J, Liu C, Aghamohhammadi A, Bergbreiter A, Du L, Lu J et al. Novel mutations in TACI (TNFRSF13B) causing common variable immunodeficiency. J Clin Immunol 2009; 29: 777–785.

    Article  CAS  PubMed  Google Scholar 

  36. Kull I, Wickman M, Lilja G, Nordvall SL, Pershagen G . Breast feeding and allergic diseases in infants-a prospective birth cohort study. Arch Dis Child 2002; 87: 478–481.

    Article  CAS  PubMed  Google Scholar 

  37. Kull I, Almqvist C, Lilja G, Pershagen G, Wickman M . Breast-feeding reduces the risk of asthma during the first 4 years of life. J Allergy Clin Immunol 2004; 114: 755–760.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Qiang Pan-Hammarström at the Division of Clinical Immunology at Karolinska Hospital, Huddinge, for TACI genotyping and valuable comments. We also thank all the children and parents participating in the BAMSE project. M Janzi was supported by an educational grant from the Health Care Sciences Postgraduate School. This research was supported by the Swedish Research Council and the EU (HEALTH-F2-2008-201549 EURO-PADnet). The BAMSE study was also supported by Stockholm County Council, The Swedish Heart and Lung Foundation and Centre for Allergy Research, Karolinska Institutet.

Author information

Authors and Affiliations

  1. Division of Clinical Immunology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

    M Janzi & L Hammarström

  2. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    E Melén, I Kull & M Wickman

  3. Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden

    E Melén

  4. Department of Paediatrics, Sach's Childrens’ Hospital, Södersjukhuset, Stockholm, Sweden

    M Wickman

Authors
  1. M Janzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Melén
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I Kull
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Wickman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Hammarström
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Hammarström.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janzi, M., Melén, E., Kull, I. et al. Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children. Genes Immun 13, 59–65 (2012). https://doi.org/10.1038/gene.2011.55

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2011.55

Keywords

This article is cited by

Search

Advanced search

Quick links