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Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus

Nature Genetics volume 15, pages 289–292 (1997)Cite this article

Abstract

Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is due to autoimmune destruction of pancreatic β-cells. Genetic susceptibility to IDDM is encoded by several loci, one of which (IDDM2) maps to a variable number of tandem repeats (VNTR) minisatellite, upstream of the insulin gene (INS)1–5. The short class I VNTR alleles (26–63 repeats) predispose to IDDM, while class III alleles (140–210 repeats) have a dominant protective effect1–6. We have reported that, in human adult4'6 and fetal7 pancreas in vivo, class III alleles are associated with marginally lower INS mRNA levels than class I, suggesting transcriptional effects of the VNTR. These may be related to type 1 diabetes pathogenesis, as insulin is the only known β-cell specific IDDM autoantigen. In search of a more plausible mechanism for the dominant effect of class III alleles, we analysed expression of insulin in human fetal thymus, a critical site for tolerance induction to self proteins. Insulin was detected in all thymus tissues examined and class III VNTR alleles were associated with 2- to 3-fold higher INS mRNA levels than class I. We therefore propose higher levels of thymic INS expression, facilitating immune tolerance induction, as a mechanism for the dominant protective effect of class III alleles.

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Authors and Affiliations

  1. The McGill University-Montreal Children's Hospital Research Institute and the Department of Pediatrics, Division of Endocrinology, McGill University, Montréal, Québec, Canada, H3H1P3

    Petros Vafiadis, Rosemarie Grabs, Cynthia G. Goodyer, Saman Wickramasinghe, Eleanor Colle & Constantin Polychronakos

  2. The Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, Oxford, OX3 7BN, UK

    Simon T. Bennett & John A. Todd

  3. Department of Human Genetics, McGill University, and the Montreal General Hospital, Montréal, Québec, Canada, H3G1A4

    Joseph Nadeau

  4. Room E-315, Montreal Children's Hospital, 2300 Tupper Street, Montréal, Québec, Canada, H3H 1P3

    Constantin Polychronakos

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  1. Petros Vafiadis
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Vafiadis, P., Bennett, S., Todd, J. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15, 289–292 (1997). https://doi.org/10.1038/ng0397-289

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