Associations of GAD65- and IA-2- autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry.
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.


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.
Vandewalle
C L
CL
Diabetes Research Center, Vrije Universiteit Brussel, Belgium.
Falorni
A
A
Lernmark
A
A
Goubert
P
P
Dorchy
H
H
Coucke
W
W
Semakula
C
C
Van der Auwera
B
B
Kaufman
L
L
Schuit
F C
FC
Pipeleers
D G
DG
Gorus
F K
FK
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D001530:Belgium; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D005969:Glutamate Dehydrogenase / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics*; D006801:Humans; D007223:Infant; D007328:Insulin / Q000235:genetics; D008297:Male; D009679:Nuclear Family; D012042:Registries; D012307:Risk Factors
D001323:Autoantibodies; D005819:Genetic Markers; D006683:HLA-DQ Antigens; C096322:ICA512 autoantibody; D007328:Insulin; D005969:Glutamate Dehydrogenase