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.
- autoimmune disease
- gene regulation
- genetic association
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