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The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus (SLE)
  1. Anna Hellquist (anna.hellquist{at}biosci.ki.se)
  1. Karolinska Institutet, Sweden
    1. Marco Zucchelli (marco.zucchelli{at}biosci.ki.se)
    1. Karolinska Institutet, Sweden
      1. Katja Kivinen (katja.kivinen{at}biosci.ki.se)
      1. Karolinska Institutet, Sweden
        1. Ulpu Saarialho-Kere (ulpu.saarialho-kere{at}helsinki.fi)
        1. University of Helsinki, Finland
          1. Sari Koskenmies (sari.koskenmies{at}hus.fi)
          1. Helsinki University Central Hospital, Finland
            1. Elisabeth Widen (elisabeth.widen{at}helsinki.fi)
            1. University of Helsinki, Finland
              1. Heikki Julkunen (heikki.julkunen{at}hus.fi)
              1. Helsinki University Hospital, Peijas Hospital, Finland
                1. Andrew Wong (a.wong{at}imperial.ac.uk)
                1. Imperial College, United Kingdom
                  1. Marja-Liisa Karjalainen-Lindsberg (marja-liisa.karjalainen-lindsberg{at}helsinki.fi)
                  1. University of Helsinki, Finland
                    1. Tiina Skoog (tiina.skoog{at}biosci.ki.se)
                    1. Karolinska Institutet, Sweden
                      1. Johanna Vendelin (johanna.vendelin{at}helsinki.fi)
                      1. University of Helsinki, Finland
                        1. Deborah S Cunninghame-Graham (deborah.cunninghame-graham{at}imperial.ac.uk)
                        1. Imperial College, United Kingdom
                          1. Timothy J Vyse (t.vyse{at}imperial.ac.uk)
                          1. Imperial College, United Kingdom
                            1. Juha Kere (juha.kere{at}biosci.ki.se)
                            1. Karolinska Institutet, Sweden
                              1. Cecilia M Lindgren (cecilia.lindgren{at}biosci.ki.se)
                              1. Karolinska Institutet, Sweden

                                Abstract

                                Background: Several members of the GIMAP gene family have been suggested to be 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 we hypothesized that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as SLE. Material and methods: To investigate this, we analyzed 7 single nucleotide polymorphisms in GIMAP5 in five independent sets of family based SLE collections, containing more than 2000 samples. Result: We found a significant increase in SLE risk associated with the most common GIMAP5 haplotype (odds ratio, OR=1.26, 95%CI 1.02-1.54, p=0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR=2.11, 95%, CI 1.09 -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 thalassemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, we treated monocytes with a number of 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, our data suggest the role of GIMAP5 in the pathogenesis of SLE.

                                • apoptosis
                                • autoimmune disease
                                • gene regulation
                                • genetic association

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