Abstract
In a large case-control study of Swedish incident type I diabetes patients and controls, 0–34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 × 10−13) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 × 10−5) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.
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Acknowledgements
The MAGENTA study was funded by Juvenile Diabetes Research Foundation International grant 1-2001-873 to ÅL. JS, BM and SB also received support from Canadian Institutes of Health Research grants NPG-64869 and ATF-66667, Natural Sciences and Engineering Research Council of Canada grants 213124-03 and 227972-00 and the Mathematics of Information Technology and Complex Systems, Canadian Networks of Centres of Excellence. JS and JG have fellowships from the Michael Smith Foundation for Health Research. CBS is supported by a grant from the Swedish Medical Research Council (K2006-72X-14740-04-3). IK is supported by a career development award from the Juvenile Diabetes Foundation International (2-2000-570). We thank William Hagopian, Mona Landin-Olsson and Jerry Palmer for access to data on the autoantibody markers.
The following authors are from the Diabetes Incidence in Sweden Study Group: Hans Arnqvist, Department of Internal Medicine, University of Linköping, Linköping; Elisabeth Björck, Department of Medicine, University Hospital, Uppsala; Jan Eriksson, Department of Medicine, University of Umeå, Umeå; Lennarth Nyström, Department of Epidemiology and Public Health, University of Umeå, Umeå; Lars Olof Ohlson, Sahlgrenska Hospital, University of Göteborg, Göteborg; Bengt Scherstén, Department of Community Health Sciences, Dahlby, University of Lund, Lund; and Jan Östman, Center for Metabolism and Endocrinology, Huddinge University Hospital, Stockholm.
The following authors are from the Swedish Childhood Diabetes Study Group, all from Departments of Pediatrics: M Aili, Halmstad; LE Bååth, Östersund; E Carlsson, Kalmar; H Edenwall, Karlskrona; G Forsander, Falun; BW Granström, Gällivare; I Gustavsson, Skellefteå; R Hanås, Uddevalla; L Hellenberg, Nyköping; H Hellgren, Lidköping; E Holmberg, Umeå; H Hörnell, Hudiksvall; Sten-A Ivarsson, Malmö; C Johansson, Jönköping; G Jonsell, Karlstad; K Kockum, Ystad; B Lindblad, Mölndal; A Lindh, Borås; J Ludvigsson, Linköping; U Myrdal, Västerås; J Neiderud, Helsingborg; K Segnestam, Eskilstuna; S Sjöblad, Lund; L Skogsberg, Boden; L Strömberg, Norrköping; U Ståhle, Ängelholm; B Thalme, Huddinge; K Tullus, Danderyd; T Tuvemo, Uppsala; M Wallensteen, Stockholm; O Westphal, Göteborg; and J Åman, Örebro.
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Shin, JH., Janer, M., McNeney, B. et al. IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5. Genes Immun 8, 503–512 (2007). https://doi.org/10.1038/sj.gene.6364413
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