Value of Antibodies to Islet Protein Tyrosine Phosphatase–Like Molecule in Predicting Type 1 Diabetes
- Mohammed Hawa,
- Rachael Rowe,
- Michael S Lan,
- Abner L Notkins,
- Paolo Pozzilli,
- Michael R Christie and
- R. David G Leslie
- Department of Diabetes and Metabolism, St. Bartholomew's HospitalLondon, U.K.
- Laboratory of Oral Medicine, National Institutes of HealthBethesda, Maryland
- Clinica Medica II, La Sapienza UniversityRome, Italy
- Department of Medicine, Kings College Hospital, London, U.K.
- Address correspondence and reprint requests to Dr. R.D.G. Leslie, Department of Diabetes, St. Bartholomew's Hospital, London EC1A 7BE, U.K.
Islet antigens associated with type 1 diabetes include a recently identified protein tyrosine phosphatase–like molecule IA-2, which contains the intracellular fragment IA-2ic. To determine whether combinations of antibodies including those to IA-2 characterize and predict type 1 diabetes, we studied antibodies to IA-2, IA-2ic, glutamic acid decarboxylase (GAD65), and islet cell antibodies (ICAs) in 1) 60 newly diagnosed type 1 diabetic patients followed for 1 year, 2) 31 monozygotic twin pairs discordant for type 1 diabetes followed up to 12 years (11 twins developed diabetes), 3) 18 dizygotic twin pairs discordant for type 1 diabetes, and 4) normal healthy control subjects. Newly diagnosed type 1 diabetic patients frequently had antibodies to IA-2 (62%), IA-2ic (67%), GAD65 (77%), and ICAs (85%). The intracellular fragment of IA-2 probably contains the immunodominant epitope as 137 of 143 samples with IA-2 antibodies from type 1 diabetic patients also had IA-2ic antibodies. Monozygotic twins were usually discordant for antibody specificities. Concordance was higher in monozygotic than matched dizygotic twins for both antibody combinations (33 vs. 6%, P < 0.05) and the development of diabetes (33 vs. 0%, P < 0.01). In monozygotic twins, all the antibodies were highly predictive of type 1 diabetes (positive predictive values all >87%), although antibodies were also detected in twins at low risk of disease. In summary, IA-2 emerges as a major antigen associated with type 1 diabetes and distinct from GAD65. Type 1 diabetes–associated autoimmunity, which is probably induced by environmental factors, does not necessarily herald progression to the disease. However, genetic factors may influence the development of combinations of disease-associated antibodies and the progression to type 1 diabetes.
- Received July 29, 1996.
- Revision received March 26, 1997.
- Accepted March 26, 1997.
- Copyright © 1997 by the American Diabetes Association