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.

  • Letter
  • Published:

Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency

Nature Genetics volume 42, pages 777–780 (2010)Cite this article

Subjects

Abstract

To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 × 10−10) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 × 10−7), and 29 additional loci were identified with P < 5 × 10−5. A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 × 10−4) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Linkage disequilibrium structure and combined association results at the IFIH1 locus.
Figure 2: Linkage disequilibrium structure and combined association results in the CLEC16A genomic region.

Similar content being viewed by others

References

  1. Casanova, J.-L. & Abel, L. Primary immunodeficiencies: a field in its infancy. Science 317, 617–619 (2007).

    Article  CAS  Google Scholar 

  2. Notarangelo, L.D. et al. Primary immunodeficiencies: 2009 update. J. Allergy Clin. Immunol. 124, 1161–1178 (2009).

    Article  CAS  Google Scholar 

  3. Conley, M.E., Notarangelo, L.D. & Etzioni, A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin. Immunol. 93, 190–197 (1999).

    Article  CAS  Google Scholar 

  4. Burrows, P.D. & Cooper, M.D. IgA deficiency. Adv. Immunol. 65, 245–276 (1997).

    Article  CAS  Google Scholar 

  5. Hammarström, L., Vorechovsky, I. & Webster, D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin. Exp. Immunol. 120, 225–231 (2000).

    Article  Google Scholar 

  6. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nat. Rev. Immunol. 3, 63–72 (2003).

    Article  CAS  Google Scholar 

  7. Cerutti, A. & Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity 28, 740–750 (2008).

    Article  CAS  Google Scholar 

  8. Cunningham-Rundles, C. Physiology of IgA and IgA Deficiency. J. Clin. Immunol. 21, 303–309 (2001).

    Article  CAS  Google Scholar 

  9. Vorechovský, I., Webster, A.D., Plebani, A. & Hammarstrom, L. Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition. Am. J. Hum. Genet. 64, 1096–1109 (1999).

    Article  Google Scholar 

  10. Vorechovský, I. et al. Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin. Immunol. Immunopathol. 77, 185–192 (1995).

    Article  Google Scholar 

  11. Price, A.L. et al. Discerning the ancestry of European Americans in genetic association studies. PLoS Genet. 4, e236 (2008).

    Article  Google Scholar 

  12. Tian, C. et al. Analysis and application of European genetic substructure using 300 K SNP information. PLoS Genet. 4, e4 (2008).

    Article  Google Scholar 

  13. Smyth, D.J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617–619 (2006).

    Article  CAS  Google Scholar 

  14. Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).

    Article  CAS  Google Scholar 

  15. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    Article  CAS  Google Scholar 

  16. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

    Article  CAS  Google Scholar 

  17. Shigemoto, T. et al. Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes. J. Biol. Chem. 284, 13348–13354 (2009).

    Article  CAS  Google Scholar 

  18. Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007).

    Article  CAS  Google Scholar 

  19. International Multiple Sclerosis Genetics Consortium (IMSGC). The expanding genetic overlap between multiple sclerosis and type I diabetes. Genes Immun. 10, 11–14 (2009).

  20. Goshen, E. et al. Antinuclear and related autoantibodies in sera of healthy subjects with IgA deficiency. J. Autoimmun. 2, 51–60 (1989).

    Article  CAS  Google Scholar 

  21. Barka, N. et al. Multireactive pattern of serum autoantibodies in asymptomatic individuals with immunoglobulin A deficiency. Clin. Diagn. Lab. Immunol. 2, 469–472 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hammarström, L., Persson, M.A. & Smith, C.I. Anti-IgA in selective IgA deficiency. In vitro effects and Ig subclass pattern of human anti-IgA. Scand. J. Immunol. 18, 509–513 (1983).

    Article  Google Scholar 

  23. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  24. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  25. Salmela, E. et al. Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe. PLoS ONE 3, e3519 (2008).

    Article  Google Scholar 

  26. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the individuals with IgAD and their physicians for their contributions to this work. These studies were supported by the US National Institutes of Health (U19 AI067152 and AR043274), the Swedish Research Council, the European Research Council (242551-ImmunoSwitch) and EURO-PADnet grant 201549. Genentech, Inc. provided partial funding for the GWAS studies. Financial support was also provided through the regional agreement on medical training and clinical research the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet between the Stockholm county council and the Karolinska Institute. R.C.F. was supported by a fellowship from the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/16281/2004). The population allele and genotype frequencies were obtained from a data source funded by the Nordic Center of Excellence in Disease Genetics based on regional samples from Finland and Sweden. The Helsinki 4 study was supported by the Yale Center for Human Genetics and Genomics and the Yale Program on Neurogenetics and US National Institutes of Health grants R01NS057756 and U24 NS051869.

Author information

Author notes

  1. Timothy W Behrens and Lennart Hammarström: These authors jointly directed this work.

Authors and Affiliations

  1. Genentech, Inc., South San Francisco, California, USA

    Ricardo C Ferreira, Robert R Graham, Vesela Gateva, Ward Ortmann, Hilary F Clark & Timothy W Behrens

  2. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden

    Qiang Pan-Hammarström & Lennart Hammarström

  3. Department of Immunology, Hospital Universitario La Paz, Madrid, Spain

    Gumersindo Fontán

  4. The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York, USA

    Annette T Lee & Peter K Gregersen

  5. Department of Clinical Immunology, Hospital Clínico San Carlos, Madrid, Spain

    Elena Urcelay, Miguel Fernández-Arquero & Concepción Núñez

  6. Landspitali–University Hospital and the Department of Medicine, University of Iceland, Reykjavik, Iceland

    Gudmundur Jorgensen & Björn R Ludviksson

  7. Finnish Red Cross Blood Service, Clinical Laboratory, Helsinki, Finland

    Sinikka Koskinen & Katri Haimila

  8. Department of Medicine, Rheumatology Unit, Karolinska Institutet at Karolinska University Solna, Stockholm, Sweden

    Lars Klareskog

Authors
  1. Ricardo C Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiang Pan-Hammarström
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert R Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vesela Gateva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gumersindo Fontán
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annette T Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ward Ortmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elena Urcelay
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Miguel Fernández-Arquero
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Concepción Núñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gudmundur Jorgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Björn R Ludviksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sinikka Koskinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Katri Haimila
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hilary F Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lars Klareskog
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peter K Gregersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Timothy W Behrens
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Lennart Hammarström
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.C.F. carried out most of the analyses for this study. T.W.B. and L.H. conceived and directed this study. G.F., E.U., M.F.-A., C.N., G.J., B.R.L., S.K., K.H., L.K., P.K.G. and L.H. performed subject diagnosis, coordinated the enrollment of subjects and provided access to genotyping datasets. A.T.L. performed sample genotyping in the laboratory of P.K.G. Q.P.-H., V.G., R.R.G., W.O. and H.F.C. contributed to data access and analysis. R.C.F., T.W.B. and L.H. wrote the manuscript with collaboration from Q.P.-H. and R.R.G. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Timothy W Behrens or Lennart Hammarström.

Ethics declarations

Competing interests

R.R.G., V.G., W.O., H.F.K. and T.W.B. are full-time employees of Genentech, Inc.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1–8 and Supplementary Note (PDF 3665 kb)

Supplementary Table 1

Additional genomic regions showing suggestive evidence for association with IgAD. (XLS 32 kb)

Supplementary Table 2

Genetic association of previously validated non-HLA autoimmunity loci in IgA. (XLS 79 kb)

Supplementary Table 4

Genetic association of loci associated with non-autoimmune phenotypes in IgAD. (XLS 26 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferreira, R., Pan-Hammarström, Q., Graham, R. et al. Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nat Genet 42, 777–780 (2010). https://doi.org/10.1038/ng.644

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.644

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