The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes
Abstract
Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4-9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas and transfected rodent cell lines, but it is difficult to reconcile the association of lower INS mRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specif…
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At the tissue level, the role of the thymus is highlighted, possibly suggesting a role of genetic variation in thymic selection of autoreactive T cells in MS.
“Interestingly, at the tissue level, the role of the thymus is also highlighted, possibly suggesting a role of genetic variation in thymic selection of autoreactive T cells in MS.(27)”
From Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility (2019) · cites this paper as [27]
Linkage analysis of sibling pairs affected by type 1 diabetes identified an area on chromosome 11p15 that was subsequently mapped to a region upstream of the insulin gene as associated with type 1 diabetes.
“In the 1990s, linkage analysis of sibling pairs affected by type 1 diabetes identified an area on chromosome 11p15 (ref. 49) that was subsequently mapped to a region upstream of the insulin gene50–52 as associated with type 1 diabetes.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [52]
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- Authors
- Pugliese, A., Zeller, M., Fernandez, A., Zalcberg, L. J., Bartlett, R. J., Ricordi, C., Pietropaolo, M., Eisenbarth, G. S., Bennett, S. T., & Patel, D. D.
- Affiliations
- University of Miami (US)
- University of Pittsburgh (US)
- Centre for Human Genetics (GB)
- Duke Medical Center (US)
- Corresponding author
- Pugliese, Alberto
- Venue
- Nature Genetics
- Published
- 1997-03
- Volume
- 15
- Issue
- 3
- Pages
- 293-297
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2026468137
- Cited by
- 945
- References
- 33
- Citations by year
- 2026: 5 · 2025: 21 · 2024: 18 · 2023: 14 · 2022: 21 · 2021: 28 · 2020: 10 · 2019: 29 · 2018: 19 · 2017: 22 · 2016: 25 · 2015: 31 · 2014: 31 · 2013: 23 · 2012: 50
- FWCI
- 18.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-33199)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- insulin gene, type 1 diabetes, INS VNTR, variable number tandem repeats, thymus, insulin mRNA expression, proinsulin, glutamic acid decarboxylase, IA-2, negative selection, T cells, diabetes susceptibility, chromosome 11p15
- MeSH terms
- Aging, Alleles, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 11, Diabetes Mellitus, Type 1, Disease Susceptibility, Embryonic and Fetal Development, Humans, Infant, Infant, Newborn, Insulin, Organ Specificity, Proinsulin, RNA, Messenger, Thymus Gland, Transcription, Genetic, Genetic Variation, Polymerase Chain Reaction, DNA Primers, Gene Expression Regulation, Developmental, Minisatellite Repeats
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