title: MHC class I chain-related gene-A is associated with IA2 and IAA but not GAD in Swedish type 1 diabetes mellitus.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Karolinska Hospital Campus, Karolinska Institute, CMM; L5:01, S-17176 Stockholm, Sweden.
authors.forename: Manu
authors.initials: M
authors.lastname: Gupta
authors.forename: Jinko
authors.initials: J
authors.lastname: Graham
authors.forename: Brian
authors.initials: B
authors.lastname: McNeeny
authors.forename: Marian
authors.initials: M
authors.lastname: Zarghami
authors.forename: Mona
authors.initials: M
authors.lastname: Landin-Olsson
authors.forename: William A
authors.initials: WA
authors.lastname: Hagopian
authors.forename: Jerry
authors.initials: J
authors.lastname: Palmer
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
authors.forename: Carani B
authors.initials: CB
authors.lastname: Sanjeevi
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000097:blood* / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D005968:Glutamate Decarboxylase / Q000097:blood; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007330:Insulin Antibodies / Q000097:blood* / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000097:blood* / Q000276:immunology; D018895:Microsatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000097:blood* / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013548:Sweden
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; D007330:Insulin Antibodies; C099187:MHC class I-related chain A; D008565:Membrane Proteins; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase