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a Department of Molecular Medicine, Karolinska Institutet, S-17176 Stockholm, Sweden b Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby V5A 1S6, Canada c Department of Medicine, University of Washington, Seattle 98195-7710, Washington d Department of Medicine, University of Lund, Lund 98108, Sweden e Pacific Northwest Research Institute, Seattle 98195, Washington
Key Words: T1DM • MICA • GAD65 • IA2 • IAA
Address for correspondence: Dr. C.B. Sanjeevi, Karolinska Institute, Department of Molecular Medicine, Karolinska Hospital Campus, CMM; L5:01, S-17176, Stockholm, Sweden. Voice: +46-8-51776254; fax: +46-8-51776179. e-mail: sanjeevi.carani{at}ki.se
In type 1 diabetes mellitus (T1DM), the frequency of antibodies against insulin (IAA), glutamic acid decarboxylase-65 (GAD65), ICA512/IA2 (IA2), and islet cell antigens (ICA) vary with human leukocyte antigen (HLA) composition of the patient. IAA, IA2 autoantibodies, and ICA are increased in DQ8 positives; GAD65 antibodies are increased in DQ2 positives. MHC class I chain-related gene-A (MICA) is another genetic marker that has been proposed to be associated with T1DM. In this article, we looked at microsatellite polymorphism of MICA and its association with autoantibodies (IAA, IA2, and GAD65) in Swedish T1DM patients and if the association explains its importance in early events in autoimmune response. We studied 635 T1DM patients between 0–35 years. Frequency of MICA5/5 was positively associated with the formation of IAA and IA2 antibodies considered individually or in combination (odds ratio [OR], 95% CI, Pc: [IAA+ versus IAA–]: 4.94, 2.09–11.62, <0.0005; [IA2+ versus IA2–]: 2.65, 1.52–4.59, 0.0015; [IAA and/or IA2+ versus rest]: 9.83, 2.37–40.78, <0.0015; [IAA and IA2+ versus rest]: 3.51, 2.01–6.15, <0.0015). Also, –5.1/5.1 was increased in IAA+ patients compared to IAA– patients (2.82, 1.64–4.83, <0.0005). All patients positive for –5/5 developed at least one of the three antibodies. Frequency of MICA5.1 was decreased in IAA+ (0.54, 0.36–0.81, 0.017), in IA2A+ (0.63, 0.45–0.88, 0.04), in IAA and/or IA2A+ (0.52, 0.33–0.84, 0.044), and in IAA and IA2A+ (0.55, 0.39–0.78, 0.0055) patients when compared with patients negative for corresponding antibodies. Frequency of MICA9, 5/5.1, and 5.1/9 was decreased in IAA+ compared to IAA– patients (0.51, 0.32–0.79, 0.021; 0.22, 0.11–0.44, <0.005; and 0.39, 0.22–0.69, 0.026, respectively). Frequency of MICA9 and –5.1/9 was also decreased in IAA and/or IA2 antibody-positive patients while MICA5/5.1 decreased in patients positive for IAA and IA2 antibody both together. IAA and IA2 antibodies are believed to appear early during the autoimmune reaction against beta cells. Thus, according to our data, MICA–5/5 and –5.1/5.1 is associated with early autoimmunity in T1DM patients. Our study suggests that MICA gene polymorphism is associated with autoantibody formation and that the polymorphism especially MICA5/5 and –5.1/5.1 are important in early events of autoimmune reaction.
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