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Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry

Nature Genetics volume 44, pages 3–5 (2012)Cite this article

To the Editor:

Recently, rare loss-of-function genetic variants in the SIAE gene, which encodes sialic acid acetylesterase, were reported to predispose to multiple autoimmune diseases1. In a pooled analysis of samples from ten autoimmune diseases, Surolia et al. identified 12 distinct nonsynonymous SIAE risk variant genotypes present in 24 of 923 affected persons (2.60%) versus 2 of 648 controls (0.31%; P = 0.0002; odds ratio of 8.6) that the authors considered to be “functionally defective SIAE alleles” because they result in defects in either esterase activity or secretion1. These nonsynonymous markers comprised one common allele frequency variant (rs78778622; encoding a p.Met89Val substitution in SIAE) and 11 rare allele frequency variants. Homozygosity for the SIAE variant (rs78778622, GG) causing the p.Met89Val alteration that resulted in a secretion-defective mutant was reported in 8 of 923 affected individuals (0.87%) but in none of the 648 control subjects1. To date, in contrast to the numerous genome-wide association studies for common variants, there have been only a few studies reporting rare variants of large effect predisposing individuals to clinically typical autoimmune disease phenotypes, despite much recent enthusiasm for exome sequencing in these genetically complex conditions.

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References

  1. Surolia, I. et al. Nature 466, 243–247 (2010).

    Article  CAS  Google Scholar 

  2. Smyth, D.J. et al. N. Engl. J. Med. 359, 2767–2777 (2008).

    Article  CAS  Google Scholar 

  3. Risch, N. & Merikangas, K. Science 273, 1516–1517 (1996).

    Article  CAS  Google Scholar 

  4. Morahan, G. et al. Diabetes 60, 1030–1040 (2011).

    Article  CAS  Google Scholar 

  5. Tarpey, P.S. et al. Nat. Genet. 41, 535–543 (2009).

    Article  CAS  Google Scholar 

  6. Durbin, R.M. et al. Nature 467, 1061–1073 (2010).

    Article  CAS  Google Scholar 

  7. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Science 324, 387–389 (2009).

    Article  CAS  Google Scholar 

  8. Trynka, G. et al. Nat. Genet. 43, 1193–1201 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

A full list of Acknowledgments is provided in the Supplementary Note.

Author information

Authors and Affiliations

  1. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Karen A Hunt, Vanisha Mistry, Nicholas A Bockett, Patrick C Dubois, Graham A R Heap & David A van Heel

  2. Department of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    Deborah J Smyth, Jason D Cooper, Sarah Nutland, Corina Shtir, Neil M Walker & John A Todd

  3. Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Tobias Balschun, Sylvia Hofmann, Stefan Schreiber & Andre Franke

  4. Department of Clinical Neurosciences, Addenbrookes Hospital, University of Cambridge, Cambridge, UK

    Maria Ban & Stephen Sawcer

  5. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK

    Tariq Ahmad

  6. Division of Genetics and Molecular Medicine, King's College London, London, UK

    Vidya Anand & Timothy J Vyse

  7. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Jeffrey C Barrett, Sarah Edkins, Sarah Hunt, Cordelia Langford, Willem Ouwehand, Simon Potter & Panos Deloukas

  8. Genome Centre, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, London, UK

    Leena Bhaw-Rosun, Kerith-Rae M Dias & Charles A Mein

  9. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford and Oxford National Institute for Health Research (NIHR) Biomedical Centre, Oxford, UK

    Oliver J Brand, Matthew J Simmonds & Stephen C L Gough

  10. Department of Rheumatology and Clinical Immunology, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands

    Elisabeth Brouwer & Marcel D Posthumus

  11. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA

    Patrick Concannon, Suna Onengut-Gumuscu & Stephen S Rich

  12. Genetics Department, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands

    Cleo C van Diemen, Karin Fransen, Gosia Trynka, Alexandra Zhernakova & Cisca Wijmenga

  13. Department of Dermatology, University Clinic Schleswig-Holstein, Campus Kiel, Kiel, Germany

    Regina Fölster-Holst & Stephan Weidinger

  14. Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    David N Glass, Marc Sudman & Susan D Thompson

  15. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    Tom W J Huizinga, Rene Toes & Alexandra Zhernakova

  16. IBD Genetics Research Group, Addenbrooke's Hospital, Cambridge, UK

    James Lee & Miles Parkes

  17. Department of Gastroenterology & Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, UK

    John Mansfield

  18. Dipartimento di Scienze Neurologiche e Cardiovascolari, Centro Sclerosi Multipla, Università di Cagliari, Cagliari, Italy

    Maria Giovanna Marrosu

  19. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK

    Christopher G Mathew & Natalie J Prescott

  20. Department of Pneumology, University Medical Center, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

    Joachim Müller-Quernheim

  21. Department of Haematology, University of Cambridge & National Health Service (NHS) Blood and Transplant, Cambridge, UK

    Willem Ouwehand & Jennifer Sambrook

  22. University College London Genomics, Institute of Child Health, University College London, London, UK

    Kerra Pearce

  23. Istituto di Neurologia Clinica, Università di Sassari, Sassari, Italy

    Giulio Rosati

  24. Division of Medical Sciences, Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

    Jack Satsangi

  25. Department of Dermatology and Allergy, Technical University Munich, Munich, Germany

    Stephan Weidinger

  26. Department of Medical Genetics, Complex Genetics Section, University Medical Centre Utrecht, Utrecht, The Netherlands

    Alexandra Zhernakova

  27. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Alexandra Zhernakova

  28. Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy

    Magdalena Zoledziewska & Francesco Cucca

  29. Department of Gastroenterology and Hepatology, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands

    Rinse K Weersma

  30. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Natzionale delle Richerche (CNR), Monserrato, Italy

    Francesco Cucca

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  1. Karen A Hunt
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Consortia

Type 1 Diabetes Genetics Consortium

UK Inflammatory Bowel Disease (IBD) Genetics Consortium

Wellcome Trust Case Control Consortium

Corresponding author

Correspondence to David A van Heel.

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Competing interests

The authors declare no competing financial interests.

Additional information

A full list of consortium members is provided in the Supplementary Note.

A full list of consortium members is provided in the Supplementary Note.

A full list of consortium members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note and Supplementary Tables 1 and 2. (PDF 188 kb)

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Hunt, K., Smyth, D., Balschun, T. et al. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Nat Genet 44, 3–5 (2012). https://doi.org/10.1038/ng.1037

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