The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.
OBJECTIVE
We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.


METHODS
A total of 686 patients diagnosed in 1996-2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.


RESULTS
Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.


CONCLUSIONS
This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
Department of Clinical Sciences, Skåne University Hospital SUS, Lund University, CRC , Malmö , Sweden.
C
C
Andersson
K
K
Larsson
F
F
Vaziri-Sani
K
K
Lynch
A
A
Carlsson
E
E
Cedervall
B
B
Jönsson
J
J
Neiderud
M
M
Månsson
A
A
Nilsson
A
A
Lernmark
H
H
Elding Larsson
S-A
SA
Ivarsson
D000293:Adolescent; D000367:Age Factors; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D027682:Cation Transport Proteins / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D012680:Sensitivity and Specificity; D012737:Sex Factors; D000075703:Zinc Transporter 8
D001323:Autoantibodies; D001324:Autoantigens; D027682:Cation Transport Proteins; D006683:HLA-DQ Antigens; C087054:ICA1 protein, human; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8