Do Non-HLA Genes Influence Development of Persistent Islet Autoimmunity and Type 1 Diabetes in Children With High-Risk HLA-DR,DQ Genotypes?
- Andrea K. Steck1,
- Weiming Zhang1,2,
- Teodorica L. Bugawan3,
- Katherine J. Barriga1,
- Alan Blair3,
- Henry A. Erlich3,
- George S. Eisenbarth1,
- Jill M. Norris2 and
- Marian J. Rewers1,2
- 1Barbara Davis Center for Childhood Diabetes, University of Colorado–Denver, Aurora, Colorado;
- 2Department of Preventive Medicine and Biometrics, University of Colorado–Denver, Aurora, Colorado;
- 3Department of Human Genetics, Roche Molecular Systems, Alameda, California.
- Corresponding author: Andrea Steck, andrea.steck{at}uchsc.edu.
Abstract
OBJECTIVE Specific alleles of non-HLA genes INS, CTLA-4, and PTPN22 have been associated with type 1 diabetes. We examined whether some of these alleles influence development of islet autoimmunity or progression from persistent islet autoimmunity to type 1 diabetes in children with high-risk HLA-DR,DQ genotypes.
RESEARCH DESIGN AND METHODS Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,449 young children carrying HLA-DR,DQ genotypes associated with type 1 diabetes. Of those, 112 have developed islet autoimmunity (persistent autoantibodies to insulin, GAD65, and/or IA-2), and 47 of these have progressed to type 1 diabetes. The influence of polymorphisms of INS(−23Hph1), CTLA-4(T17A), and PTPN22(R620W) on development of persistent islet autoimmunity and progression to type 1 diabetes was evaluated by parametric models and by survival analyses.
RESULTS PTPN22(R620W) allele T was associated with development of persistent islet autoimmunity (hazard ratio 1.83 [95% CI 1.27–2.63]) controlling for ethnicity, presence of HLA-DR3/4,DQB1*0302, and having a first-degree relative with type 1 diabetes. Survival analyses showed a significantly (P = 0.002) higher risk of persistent islet autoimmunity by age 10 years for the TT genotype (27.3%) than for the CT or CC genotype (7.9 and 5.3%, respectively). Cumulative risk of persistent islet autoimmunity was slightly higher (P = 0.02) for the INS(−23Hph1) AA genotype (7.8%) than for the AT or TT genotype (4.2 and 6.4% risk by age 10 years, respectively).
CONCLUSIONS Whereas the HLA-DR3/4,DQB1*0302 genotype had a dramatic influence on both development of islet autoimmunity and progression to type 1 diabetes, the PTPN22(R620W) T allele significantly influences progression to persistent islet autoimmunity in the DAISY cohort.
Footnotes
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- Received August 27, 2008.
- Accepted January 19, 2009.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
- © 2009 by the American Diabetes Association.
