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Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis

A Corrigendum to this article was published on 01 April 2009

This article has been updated

Abstract

Sarcoidosis is a complex chronic inflammatory disorder with predominant manifestation in the lung. In the first genome-wide association study (>440,000 SNPs) of this disease, comprising 499 German individuals with sarcoidosis and 490 controls, we detected a series of genetic associations. The strongest association signal maps to the ANXA11 (annexin A11) gene on chromosome 10q22.3. Validation in an independent sample (1,649 cases, 1,832 controls) confirmed the association (SNP rs2789679: P = 3.0 × 10−13, rs7091565: P = 1.0 × 10−5, allele-based test). Extensive fine mapping located the association signal to a region between exon 5 and exon 14 of ANXA11. A common nonsynonymous SNP (rs1049550, C > T, R230C) was found to be strongly associated with sarcoidosis. The GWAS lead SNP and additional risk variants in the region (rs1953600, rs2573346, rs2784773) were in strong linkage disequilibrium with rs1049550. Annexin A11 has complex and essential functions in several biological pathways, including apoptosis and proliferation.

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Figure 1: Significance of disease association and LD structure in the 10q22.3 region.
Figure 2: Expression and localization of ANXA11 in human tissues.
Figure 3: Schematic presentation of the annexin A11 protein.

Change history

  • 24 March 2009

    NOTE: In the version of this article initially published, the SNP rs1049550 listed in the abstract was indicated incorrectly as a T>C change. It is a C>T change. On the third page of the article, the haplotype containing rs1049550 was incorrectly listed as TATACC. It should be AGCATT. These errors have been corrected in the HTML and PDF versions of the article.

References

  1. Iannuzzi, M.C., Rybicki, B.A. & Teirstein, A.S. Sarcoidosis. N. Engl. J. Med. 357, 2153–2165 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Baughman, R.P., Lower, E.E. & du Bois, R.M. Sarcoidosis. Lancet 361, 1111–1118 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Schürmann, M. et al. Results from a genome-wide search for predisposing genes in sarcoidosis. Am. J. Respir. Crit. Care Med. 164, 840–846 (2001).

    Article  PubMed  Google Scholar 

  4. Iannuzzi, M.C. et al. Genome-wide search for sarcoidosis susceptibility genes in African Americans. Genes Immun. 6, 509–518 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Gray-McGuire, C. et al. Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5. Hum. Genet. 120, 420–430 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Rybicki, B.A. et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am. J. Hum. Genet. 77, 491–499 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li, Y. et al. BTNL2 gene variant and sarcoidosis. Thorax 61, 273–274 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Stenzel, A. et al. Patterns of linkage disequilibrium in the MHC region on human chromosome 6p. Hum. Genet. 114, 377–385 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Valentonyte, R. et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat. Genet. 37, 357–364 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Tomas, A. & Moss, S.E. Calcium- and cell cycle-dependent association of annexin 11 with the nuclear envelope. J. Biol. Chem. 278, 20210–20216 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Hayes, M., Longbottom, R., Evans, M. & Moss, S. Annexinopathies. Subcell. Biochem. 45, 1–28 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Jorgensen, C. et al. Determination of autoantibodies to annexin XI in systemic autoimmune diseases. Lupus 9, 515–520 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Gerke, V. & Moss, S.E. Annexins: from structure to function. Physiol. Rev. 82, 331–371 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Moss, S. & Morgan, R. The annexins. Genome Biol. 5, 219 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tokumitsu, H., Mizutani, A. & Hidaka, H. Calcyclin-binding site located on the NH2-terminal domain of rabbit CAP-50 (annexin-XI): functional expression of CAP-50 in Escherichia coli. Arch. Biochem. Biophys. 303, 302–306 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Satoh, H., Shibata, H., Nakano, Y., Kitaura, Y. & Maki, M. ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca2+-dependent manner. Biochem. Biophys. Res. Commun. 291, 1166–1172 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Leclerc, E., Fritz, G., Weibel, M., Heizmann, C.W. & Galichet, A. S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J. Biol. Chem. 282, 31317–31331 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Vito, P., Lacaná, E. & D'Adamio, L. Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 271, 521–525 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Lacana, E., Ganjei, J., Vito, P. & D'Adamio, L. Dissociation of apoptosis and activation of IL-1beta-converting enzyme/Ced-3 proteases by ALG-2 and the truncated Alzheimer's gene ALG- 3. J. Immunol. 158, 5129–5135 (1997).

    CAS  PubMed  Google Scholar 

  20. Missotten, M., Nichols, A., Rieger, K. & Sadoul, R. Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein. Cell Death Differ. 6, 124–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Rao, R.V. et al. Molecular components of a cell death pathway activated by endoplasmic reticulum stress. J. Biol. Chem. 279, 177–187 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Joo, J.H. et al. S100A6 (calcyclin) enhances the sensitivity to apoptosis via the upregulation of caspase-3 activity in Hep3B cells. J. Cell. Biochem. 103, 1183–1197 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Tagaya, Y., Bamford, R.N., DeFilippis, A.P. & Waldmann, T.A. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4, 329–336 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Bulfone-Paus, S. et al. Interleukin-15 protects from lethal apoptosis in vivo. Nat. Med. 3, 1124–1128 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Agostini, C. et al. Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J. Immunol. 157, 910–918 (1996).

    CAS  PubMed  Google Scholar 

  26. Jullien, D. et al. IL-15, an immunomodulator of T cell responses in intracellular infection. J. Immunol. 158, 800–806 (1997).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank all individuals with sarcoidosis, families and physicians for their cooperation. The efforts of the German Sarcoidosis Patients Organization (Deutsche Sarkoidose-Vereinigung) and the contribution of pulmonary specialist physicians are gratefully acknowledged. The authors wish to thank T. Wienker, M. Steffens, M. Albrecht, T. Wesse and C. von der Lanken for expert technical help, R. Kleindorp and G. Richter for logistic help, and R. Vogler for database and computer support. This study was funded by the German National Genome Research Network (NGFN-2).

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Authors and Affiliations

Authors

Contributions

S.H. performed the SNP selection, genotyping and data analysis, drafted the manuscript and prepared the tables and parts of the figures; A.Franke and A.Fischer helped with data analysis and contributed to the design and the writing of the manuscript; G.J. and P.R. performed the protein, immunohistochemistry and cDNA experiments and contributed to the manuscript; M.K. supervised the statistical analysis and edited the paper; M.N. performed the haplotype analysis and helped with data analysis; M.S. and J.M.-Q. coordinated the recruitment, collected the phenotype data and contributed to the writing of the manuscript; K.I.G. provided the bronchoalveolar lavage and transbronchial biopsy samples; S.H. and S.S. jointly designed and supervised the experiment and wrote the manuscript.

Corresponding author

Correspondence to Stefan Schreiber.

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Supplementary Methods, Supplementary Tables 1–3, Supplementary Figures 1–4 (PDF 1173 kb)

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Hofmann, S., Franke, A., Fischer, A. et al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet 40, 1103–1106 (2008). https://doi.org/10.1038/ng.198

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