Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele

Simon T. Bennett, Amanda J. Wilson, Laura Esposito, Nourdine Bouzekri, Dag E. Undlien, Francesco Cucca, Lorenza Nisticò, Raffaella Buzzetti, Emanuele Bosi, Flemming Pociot, Jørn Nerup, Anne Cambon-Thomsen, Alberto Pugliese, Julian P H Shield, Patricia A. McKinney, Stephen C. Bain, Constantin Polychronakos, John A. Todd, P. Pozzilli, N. VisalliM. Baroni, E. Fioriti, C. Mesturino, A. Signore, M. Cavallo, L. Lucentini, M. Matteoli, A. Crinó, 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. De Mattia, M. Cassone Faldetta, O. Laurenti, G. Marietti, D. Pitocco, F. Ferrazzoli, C. Bizzarri, G. Ghirlanda

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians; INS VNTR alleles divide into two discrete size classes. 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 protective. 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 pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. 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 imprinting. 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, trans- 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.

Original languageEnglish
Pages (from-to)350-352
Number of pages3
JournalNature Genetics
Volume17
Issue number3
DOIs
StatePublished - Nov 17 1997

Fingerprint

Type 1 Diabetes Mellitus
Alleles
Insulin
Chromosomes
Immune Tolerance
Inborn Genetic Diseases
Autoantigens
Medical Genetics
Regulator Genes
Epigenomics
Fathers
Thymus Gland
Genes
Yeasts
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Bennett, S. T., Wilson, A. J., Esposito, L., Bouzekri, N., Undlien, D. E., Cucca, F., ... Ghirlanda, G. (1997). Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. Nature Genetics, 17(3), 350-352. https://doi.org/10.1038/ng1197-350

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. / Bennett, Simon T.; Wilson, Amanda J.; Esposito, Laura; Bouzekri, Nourdine; Undlien, Dag E.; Cucca, Francesco; Nisticò, Lorenza; Buzzetti, Raffaella; Bosi, Emanuele; Pociot, Flemming; Nerup, Jørn; Cambon-Thomsen, Anne; Pugliese, Alberto; Shield, Julian P H; McKinney, Patricia A.; Bain, Stephen C.; Polychronakos, Constantin; Todd, John A.; Pozzilli, P.; Visalli, N.; Baroni, M.; Fioriti, E.; Mesturino, C.; Signore, A.; Cavallo, M.; Lucentini, L.; Matteoli, M.; Crinó, A.; Teodonio, C.; Amoretti, R.; Tombesi, A.; Ruggeri, M.; Pisano, L.; Suraci, C.; Pennafina, M.; Boscherini, B.; Stoduto, S.; Fonte, M.; Mancabitti, M.; Multari, G.; Suppa, M.; De Mattia, G.; Cassone Faldetta, M.; Laurenti, O.; Marietti, G.; Pitocco, D.; Ferrazzoli, F.; Bizzarri, C.; Ghirlanda, G.

In: Nature Genetics, Vol. 17, No. 3, 17.11.1997, p. 350-352.

Research output: Contribution to journalArticle

Bennett, ST, Wilson, AJ, Esposito, L, Bouzekri, N, Undlien, DE, Cucca, F, Nisticò, L, Buzzetti, R, Bosi, E, Pociot, F, Nerup, J, Cambon-Thomsen, A, Pugliese, A, Shield, JPH, McKinney, PA, Bain, SC, Polychronakos, C, Todd, JA, Pozzilli, P, Visalli, N, Baroni, M, Fioriti, E, Mesturino, C, Signore, A, Cavallo, M, Lucentini, L, Matteoli, M, Crinó, A, Teodonio, C, Amoretti, R, Tombesi, A, Ruggeri, M, Pisano, L, Suraci, C, Pennafina, M, Boscherini, B, Stoduto, S, Fonte, M, Mancabitti, M, Multari, G, Suppa, M, De Mattia, G, Cassone Faldetta, M, Laurenti, O, Marietti, G, Pitocco, D, Ferrazzoli, F, Bizzarri, C & Ghirlanda, G 1997, 'Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele', Nature Genetics, vol. 17, no. 3, pp. 350-352. https://doi.org/10.1038/ng1197-350
Bennett ST, Wilson AJ, Esposito L, Bouzekri N, Undlien DE, Cucca F et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. Nature Genetics. 1997 Nov 17;17(3):350-352. https://doi.org/10.1038/ng1197-350
Bennett, Simon T. ; Wilson, Amanda J. ; Esposito, Laura ; Bouzekri, Nourdine ; Undlien, Dag E. ; Cucca, Francesco ; Nisticò, Lorenza ; Buzzetti, Raffaella ; Bosi, Emanuele ; Pociot, Flemming ; Nerup, Jørn ; Cambon-Thomsen, Anne ; Pugliese, Alberto ; Shield, Julian P H ; McKinney, Patricia A. ; Bain, Stephen C. ; Polychronakos, Constantin ; Todd, John A. ; Pozzilli, P. ; Visalli, N. ; Baroni, M. ; Fioriti, E. ; Mesturino, C. ; Signore, A. ; Cavallo, M. ; Lucentini, L. ; Matteoli, M. ; Crinó, A. ; Teodonio, C. ; Amoretti, R. ; Tombesi, A. ; Ruggeri, M. ; Pisano, L. ; Suraci, C. ; Pennafina, M. ; Boscherini, B. ; Stoduto, S. ; Fonte, M. ; Mancabitti, M. ; Multari, G. ; Suppa, M. ; De Mattia, G. ; Cassone Faldetta, M. ; Laurenti, O. ; Marietti, G. ; Pitocco, D. ; Ferrazzoli, F. ; Bizzarri, C. ; Ghirlanda, G. / Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. In: Nature Genetics. 1997 ; Vol. 17, No. 3. pp. 350-352.
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AU - Undlien, Dag E.

AU - Cucca, Francesco

AU - Nisticò, Lorenza

AU - Buzzetti, Raffaella

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AU - Nerup, Jørn

AU - Cambon-Thomsen, Anne

AU - Pugliese, Alberto

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AU - Polychronakos, Constantin

AU - Todd, John A.

AU - Pozzilli, P.

AU - Visalli, N.

AU - Baroni, M.

AU - Fioriti, E.

AU - Mesturino, C.

AU - Signore, A.

AU - Cavallo, M.

AU - Lucentini, L.

AU - Matteoli, M.

AU - Crinó, A.

AU - Teodonio, C.

AU - Amoretti, R.

AU - Tombesi, A.

AU - Ruggeri, M.

AU - Pisano, L.

AU - Suraci, C.

AU - Pennafina, M.

AU - Boscherini, B.

AU - Stoduto, S.

AU - Fonte, M.

AU - Mancabitti, M.

AU - Multari, G.

AU - Suppa, M.

AU - De Mattia, G.

AU - Cassone Faldetta, M.

AU - Laurenti, O.

AU - Marietti, G.

AU - Pitocco, D.

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AU - Bizzarri, C.

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