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J Med Genet 44:314-321 doi:10.1136/jmg.2006.046185
  • Original article

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

  1. Anna Hellquist1,2,*,
  2. Marco Zucchelli1,*,
  3. Katja Kivinen1,
  4. Ulpu Saarialho-Kere3,4,
  5. Sari Koskenmies3,5,
  6. Elisabeth Widen6,
  7. Heikki Julkunen7,
  8. Andrew Wong8,
  9. Marja-Liisa Karjalainen-Lindsberg9,
  10. Tiina Skoog1,2,
  11. Johanna Vendelin5,
  12. Deborah S Cunninghame-Graham8,
  13. Timothy J Vyse8,
  14. Juha Kere1,2,5,
  15. Cecilia M Lindgren1
  1. 1Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden
  2. 2Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden
  3. 3Department of Dermatology, University of Helsinki, Helsinki, Finland
  4. 4Department of Dermatology, Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden
  5. 5Department of Medical Genetics, University of Helsinki, Finland
  6. 6Finnish Genome Center, University of Helsinki, Helsinki, Finland
  7. 7Department of Medicine, Peijas Hospital and Helsinki University Hospital, Helsinki, Finland
  8. 8Rheumatology Section, Imperial College, Hammersmith Hospital, London, UK
  9. 9Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
  1. Correspondence to:
 Professor Juha Kere
 Karolinska Institutet, Department of Biosciences and Nutrition, S-141 57 Huddinge, Sweden; juha.kere{at}biosci.ki.se
  • Received 30 August 2006
  • Accepted 16 December 2006
  • Revised 26 November 2006
  • Published Online First 12 January 2007

Abstract

Background: Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods: To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family-based SLE collections, containing more than 2000 samples.

Result: A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non-terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion: Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.

Footnotes

  • * These authors contributed equally to the manuscript

  • Published Online First 12 January 2007

  • Competing interests: None.