TY - JOUR
T1 - Only multiple autoantibodies to islet cells (ICA), insulin, GAD65, IA-2 and IA-2β predict immune-mediated (type 1) diabetes in relatives
AU - Maclaren, Noel
AU - Lan, Michael
AU - Coutant, Regis
AU - Schatz, Desmond
AU - Silverstein, Janet
AU - Muir, Andrew
AU - Clare-Salzer, Michael
AU - She, Jin-Xiong
AU - Malone, John
AU - Crockett, Samual
AU - Schwartz, Sherwyn
AU - Quattrin, Teresa
AU - Desilva, Mark
AU - Vander Vegt, Pierre
AU - Notkins, Abner
AU - Krischer, Jeffrey
N1 - Funding Information:
This study was supported by grants RO1 HD 19469; GCRC MO1 RR00082 from the National Institutes of Health; American Diabetes Association Mentor Award and a gift-in-aid from Sydney Kriser.
PY - 1999/6
Y1 - 1999/6
N2 - We report here our prospective study of 15,224 non-diabetic, first- degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2β autoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2βA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5- year risk=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year risk=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2β A. Loss of first phase insulin release to IVGTT also occurred only in those ICA- positive relatives who had one or more of the other autoantibodies. The data suggests that significant β-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.
AB - We report here our prospective study of 15,224 non-diabetic, first- degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2β autoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2βA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5- year risk=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year risk=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2β A. Loss of first phase insulin release to IVGTT also occurred only in those ICA- positive relatives who had one or more of the other autoantibodies. The data suggests that significant β-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.
KW - Autoantibodies
KW - GAD65
KW - HLA- DR/DQ
KW - IA-2
KW - IA-2β
KW - Prediction
KW - Relatives
KW - Type 1 diabetes
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U2 - 10.1006/jaut.1999.0281
DO - 10.1006/jaut.1999.0281
M3 - Article
C2 - 10330299
AN - SCOPUS:0033020127
SN - 0896-8411
VL - 12
SP - 279
EP - 287
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
IS - 4
ER -