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


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.


RESULTS
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).


CONCLUSIONS
Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.
Hellquist
Anna
A
Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden.
Zucchelli
Marco
M
Kivinen
Katja
K
Saarialho-Kere
Ulpu
U
Koskenmies
Sari
S
Widen
Elisabeth
E
Julkunen
Heikki
H
Wong
Andrew
A
Karjalainen-Lindsberg
Marja-Liisa
ML
Skoog
Tiina
T
Vendelin
Johanna
J
Cunninghame-Graham
Deborah S
DS
Vyse
Timothy J
TJ
Kere
Juha
J
Lindgren
Cecilia M
CM
D016207:Cytokines / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005787:Gene Frequency / Q000187:drug effects; D005819:Genetic Markers / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000187:drug effects; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D015201:Meta-Analysis as Topic; D009000:Monocytes / Q000187:drug effects; D016017:Odds Ratio; D026723:Polyadenylation / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D020298:U937 Cells
D016207:Cytokines; C484030:GIMAP5 protein, human; D005819:Genetic Markers; D012333:RNA, Messenger; D019204:GTP-Binding Proteins