title: Doubly Reactive INS-IGF2 Autoantibodies in Children with Newly Diagnosed Autoimmune (type 1) Diabetes.
abstract: The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Kanatsuna
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Delli
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.|Department of Pediatrics, Östersund Hospital, Östersund, Sweden.
authors.forename: A-L
authors.initials: AL
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Vaziri-Sani
authors.affiliation: Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Larsson
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.affiliation: Department of Pediatrics, Ängelholm Hospital, Ängelholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Cedervall
authors.affiliation: Department of Pediatrics, Ystad Hospital, Ystad, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Jönsson
authors.affiliation: Department of Pediatrics, Helsingborg Hospital, Helsingborg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Neiderud
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Elding Larsson
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: S-A
authors.initials: SA
authors.lastname: Ivarsson
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Törn
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Fex
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
authors.forename: Å
authors.initials: Å
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D007328:Insulin / Q000276:immunology; D008297:Male; D050506:Mutant Chimeric Proteins / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; C584675:INS-IGF2 protein, human; D007328:Insulin; D050506:Mutant Chimeric Proteins