Associations of GAD65- and IA-2-Autoantibodies With Genetic Risk Markers in New-Onset IDDM Patients and Their Siblings. The Belgian Diabetes Registry

Christina L Vandewalle; Alberto Falorni; Åke Lernmark; Patrick Goubert; Harry Dorchy; Willy Coucke; Crispin Semakula; Bart Van Der Auwera; Leon Kaufman; Frans C Schuit; Daniël G Pipeleers; Frans K Gorus

doi:10.2337/diacare.20.10.1547

Original Articles

Associations of GAD65- and IA-2-Autoantibodies With Genetic Risk Markers in New-Onset IDDM Patients and Their Siblings. The Belgian Diabetes Registry

Christina L Vandewalle, MD,
Alberto Falorni, MD, PHD,
Åke Lernmark, MD, PHD,
Patrick Goubert,
Harry Dorchy, MD, PHD,
Willy Coucke, MD,
Crispin Semakula, MD,
Bart Van Der Auwera, MD,
Leon Kaufman, MSC, PHD,
Frans C Schuit, MD, PHD,
Daniël G Pipeleers, MD, PHD and
Frans K Gorus, MD, PHD

Diabetes Research Center Heilig Hartziekenhuis, Roeselare, Belgium; and the Belgian Diabetes Registry, Brussels, Belgium
Department of Biostatistics Heilig Hartziekenhuis, Roeselare, Belgium; and the Belgian Diabetes Registry, Brussels, Belgium
Vrije Universiteit Brussel Brussels, Belgium Department of Internal Medicine Heilig Hartziekenhuis, Roeselare, Belgium; and the Belgian Diabetes Registry, Brussels, Belgium
University of Perugia Perugia, Italy Department of Medicine Heilig Hartziekenhuis, Roeselare, Belgium; and the Belgian Diabetes Registry, Brussels, Belgium
University of Washington Seattle Department of Diabetology Heilig Hartziekenhuis, Roeselare, Belgium; and the Belgian Diabetes Registry, Brussels, Belgium
Hopital Universitaire des Enfants Reine Fabiola, Universite Libre de Bruxelles Brussels, Belgium Department of Internal Medicine Heilig Hartziekenhuis, Roeselare, Belgium; and the Belgian Diabetes Registry, Brussels, Belgium

Address correspondence and reprint requests to Frans K. Gorus, MD, PhD, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.

Diabetes Care 1997 Oct; 20(10): 1547-1552. https://doi.org/10.2337/diacare.20.10.1547

Abstract

OBJECTIVE To investigate the association of GAD (65-kDa) autoantibodies (GAD65-Abs) and IA-2 autoantibodies (IA-2-Abs) with human leukocyte antigen (HLA)-DQ and insulin gene (INS) risk markers in patients with recent-onset IDDM and their siblings.

RESEARCH DESIGN AND METHODS Blood was sampled from 608 recent-onset IDDM patients and 480 siblings, aged 0–39 years and consecutively recruited by the Belgian Diabetes Registry, to determine GAD65- and IA-2-Ab (radiobinding assay), HLA-DQ- (allele-specific oligonucleotyping), and INS-genotypes (restriction fragment length polymorphism analysis; siblings, n = 439).

RESULTS At the onset of IDDM, GAD65-Abs were preferentially associated with two populations at genetic risk but only in the 20- to 39-year age-group: 1) their prevalence was higher in carriers of DQA1*0301-DQB1*0302 (88 vs. 73% in non[DQA1*0301-DQB1*0302], P = 0.001), and 2) an association was found in patients lacking this haplotype but carrying DQA1*0501-DQB1*0201, together with INS I/I (87 vs. 54% vs. non[INS I/I], P = 0.003). Siblings of IDDM patients also presented the association of GAD65-Abs with DQA1*0301-DQB1*0302 (13 vs. 2% non[DQA1*0301-DQB1*0302], P < 0.001), while associations with the second genetic risk group could not yet be assessed. At the onset of IDDM, IA-2-Ab prevalence was higher in carriers of DQA1*0301-DQB1*0302 (69 vs. 39% non[DQA1*0301-DQB1*0302], P < 0.001) but not of DQA1*0501-DQB1*0201 or INS I/I. This association was present in both the 0- to 19- and the 20- to 39-year age-groups. It was also found in siblings of IDDM patients (4 vs. 0% non[DQA1*0301-DQB1*0302], P < 0.001).

CONCLUSIONS Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.