The IDDM2 type 1 diabetes susceptibility locus was mapped to1–6 and identified as7 allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes1. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective8. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis9,10. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects2,7,11–14 and possible allelic heterogeneity within the two defined allele classes7,15. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting16. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, frans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

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Author notes

    P. Pozzilli, N. Visalli, M. Baroni, E. Fioriti, C. Mesturino, A. Signore, M. Cavallo, L. Lucentini, M. Matteoli, A. Grind, C. Teodonio, R. Amoretti,A. Tombesi, M. Ruggeri, L. Pisano, C. Suraci, M. Pennafina, B. Boscherini, S. Stoduto, M. Fonte, M. Mancabitti, G. Multari, M. Suppa, G. DeMattia,M. Cassone Faldetta, O. Laurenti, G. Marietti, D. Pitocco, F. Ferrazzoli, C. Bizzarri & G. Ghirlanda


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

    • Simon T. Bennett
    • , Amanda J. Wilson
    • , Laura Esposito
    • , Francesco Cucca
    •  & John A. Todd
  2. CNRS UPR8291, Centre d'lmmunopathologie et de génétique humaine, Hôpital Purpan, 31300 Toulouse, France.

    • Nourdine Bouzekri
    •  & Anne Cambon-Thomsen
  3. Institute of Transplantation Immunology, The National Hospital, N-0027 Oslo, Norway.

    • Dag E. Undlien
  4. Department of Paediatrics, S. Michele Hospital, Via Peretti, Cagliari, Sardinia, Italy.

    • Francesco Cucca
  5. Endocrinologia, Instituto Clinica Medica II, University of Rome ‘La Sapienza’, 00161 Rome, Italy.

    • Lorenza Nisticò
    •  & Raffaella Buzzetti
  6. Department of Internal Medicine, Istituto Scientifico San Raffaele, University of Milan, Milan, Italy.

    • Emanuele Bosi
  7. Steno Diabetes Center, DK-2820, Gentofte, Denmark.

    • Flemming Pociot
    •  & Jørn Nerup
  8. Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida 33136, USA.

    • Alberto Pugliese
  9. Institute of Child Health, University of Bristol, Royal Hospital for Sick Children, Bristol BS2 8BJ, UK.

    • Julian P.H. Shield
  10. Paediatric Epidemiology Group, Research School of Medicine, University of Leeds, Leeds LS29LN, UK.

    • Patricia A. McKinney
  11. Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 555, UK.

    • Stephen C. Bain
  12. Montreal Children's Hospital, Montréal, Québec H3H1A4, Canada.

    • Constantin Polychronakos


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Correspondence to Simon T. Bennett or John A. Todd.

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