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Walter, M.C.* ; Albert, E.* ; Conrad, M.* ; Keller, E.* ; Hummel, M.* ; Ferber, K.* ; Barratt, B.J.* ; Todd, J.A.* ; Ziegler, A.-G.* ; Bonifacio, E.*

IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity.

Diabetologia 46, 712-720 (2003)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
AIM/HYPOTHESIS: Type 1 diabetes (T1D) is an autoimmune disease with multiple susceptibility genes. The aim of this study was to determine whether combining IDDM1/HLA and IDDM2/ insulin( INS) 5' variable number of tandem repeat locus (VNTR) genotypes improves T1D risk assessment. METHODS: Patients with T1D (n=488), control subjects (n=846), and offspring of parents with T1D (n=1122) were IDDM1 and IDDM2 genotyped. Offspring were followed for islet autoantibodies and T1D from birth until the age of 2 to 12 years. RESULTS: Compared to the I/I INS VNTR genotype, the I/III and III/III genotypes reduced T1D risk conferred by IDDM1/HLA in all HLA genotype categories of the case-control cohort by 1.6-fold to three-fold. The highest T1D risk was associated with INS VNTR class I/I plus HLA DR3/DR4-DQ8 (20.4% in patients, 0.6% in control subjects) or HLA DR4-DQ8/DR4-DQ8 (6.3% in patients, 0.2% in control subjects). In the offspring, HLA DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 conferred increased risk for early development of islet autoantibodies (14.6% and 12.9% by age 2 years). Offspring with these high risk IDDM1 genotypes plus the INS VNTR class I/I genotype (n=71; 6.3%) had the highest risk of developing islet autoantibodies (21.8% by age 2 years vs 8.9% in offspring with high risk IDDM1 plus INS VNTR class I/III or III/III genotypes, p<0.05) and T1D (8.5% by age 6 years vs 4.3%). Offspring who developed autoantibodies to multiple antigens had increased frequencies of both high risk IDDM1 and IDDM2 genotypes (p<0.0001), whereas offspring who developed autoantibodies to GAD only had increased frequencies of high risk IDDM1 and protective IDDM2 genotypes, suggesting that IDDM2 influences the autoimmune target specificity. CONCLUSION/INTERPRETATION: Combining IDDM1 and IDDM2 genotyping identifies a minority of children with an increased T1D risk.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 46, Issue: 5, Pages: 712-720 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Institute of Diabetes and Obesity (IDO)
Institute of Diabetes Research (IDF)
Institute of Pancreatic Islet Research (IPI)