Genetic Effects on Age-Dependent Onset and Islet Cell Autoantibody Markers in Type 1 Diabetes
- Jinko Graham1,
- William A. Hagopian2,
- Ingrid Kockum3,
- Lou Sheng Li3,
- Carani B. Sanjeevi3,
- Robert M. Lowe4,
- Jonathan B. Schaefer4,
- Marjan Zarghami4,
- Heather L. Day4,
- Mona Landin-Olsson5,
- Jerry P. Palmer4,
- Marta Janer-Villanueva6,
- Leroy Hood6,
- Göran Sundkvist7,
- Åke Lernmark4,
- Norman Breslow8,
- Gisela Dahlquist9,
- for the Swedish Childhood Diabetes Study Group,
- Göran Blohmé10 and
- for the Diabetes Incidence in Sweden Study Group
- 1Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, Canada
- 2Pacific Northwest Research Institute, Seattle, Washington
- 3Karolinska Institute, Department of Molecular Medicine, Stockholm, Sweden
- 4Department of Medicine, University of Washington, Seattle, Washington
- 5Department of Medicine, University of Lund, Lund, Sweden
- 6Institute for Systems Biology, Seattle, Washington
- 7Department of Endocrinology, University Hospital Malmö, University of Lund, Lund, Sweden
- 8Department of Biostatistics, University of Washington, Seattle, Washington
- 9Department of Paediatrics, Umeå University, Umeå, Sweden
- 10Diabetes Center, Södersjukhuset, Stockholm, Sweden
Abstract
Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0–34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3′ end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.
Footnotes
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Address correspondence and reprint requests to Åke Lernmark, University of Washington Department of Medicine, R.H. Williams Laboratory, 1959 N.E. Pacific St., Box 357710 Seattle, WA 98195-7710. E-mail: ake{at}u.washington.edu.
Received for publication 15 November 2001 and accepted in revised form 24 January 2002.
*Authors are listed in the acknowledgments.
GADA, GAD65 autoantibody; IA-2A, ICA512/IA-2 autoantibody; IAA, insulin autoantibody; ICA islet cell autoantibody; IRD, infrared dye; JDF, Juvenile Diabetes Foundation; VNTR, variable number tandem repeat, WHO, World Health Organization.
- DIABETES
