Abstract
The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1–kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By ‘cross–match’ haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent–of–origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Todd, J.A. The emperor's new genes: 1993 RD Lawrence lecture. Diabetic Med. 11, 6–16 (1994).
Karvonen, M., Tuomilehto, J., Libman, I. & LaPorte, R.A. A review of the recent epidemiologioal data on the worldwide incidence of type 1 (Insulin-dependent) diabetes mellitus. Diabetologia 36, 883–892 (1993).
Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 (1994).
Hashimoto, L. et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 371, 161–164 (1994).
Field, L.L., Tobias, R. & Magnus, T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 8, 189–194 (1994).
Copeman, J.B. et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31 -q33. Nature Genet. 9, 80–85 (1995).
Sheehy, M.J. HLA and insulin dependent diabetes.Diabetes 41, 123–129 (1992).
Bell, G.I., Hortta, S. & Karam, J.H. Apolymorphlc locus near the human insulin gene is associated with Insulin-dependent diabetes mellitus. Diabetes 33, 176–83 (1984).
Juller, C. et al. lnsulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155–159 (1991).
Bain, S.C. et al. Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nature Genet. 2, 212–215 34. (1992).
Lucassen, A.M. et al. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 -Kb segment of DNA spanning the insulin gene and associated VNTR. Nature Genet. 4, 305–310 (1993).
Owerbach, D. & Gabbay, K.H. Localization of a type 1 diabete ssusceptibility locus to the variable tandem repeat region flanking the insulin gene. Diabetes 42, 1708–1714 (1993).
Pritchard, L.E. et al. Analysis of the CD3 region and type 1 diabetes: application of fluorescence-based technology to linkage disequilibrium mapping. Hum. molec Genet, 4, 197–202 (1995).
Bell, G.I., Selby, M.J. & Rutter, W.J. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295, 31–35 (1982).
Pugliese, A., Awdeh, Z.L., Alper, C.A., Jackson, R.A. & Eisenbarth, G.S. The paternally inherited insulin gene B allele (1, 428 Fokl site) confers protection from insulin-dependent diabetes in families. J. Autoimmun. 7, 687–694 (1994).
Ma Bui, M., Muir, A., Maclaren, N. & She, J. Linkage of the insulin gene (INS) with insulin-dependent (IDD) in Caucasians suggest a maternal imprinting effect. Diabetes 42 (suppl. 1), 63A (1993).
Heame, C.M., Ghosh, S. & Todd, J.A. Microsatellites for linkage analysis of genetic traits. Trends Genet. 8, 288–294 (1992).
Cox, N.J., Bell, G.I. & Xiang, K. Linkage disequilibrium in the human insulin/insulin-like growth factor II region of human chromosome II. Am. J. hum. Genet. 43, 495–501 (1988).
McGinnis, R.E. & Spielman, R.S. Linkage disequilibrium in the insulin gene region: size variation at the 5' flanking polymorphism and bimodality among “class I” alleles. Am. J. hum. Genet. 55, 526–532 (1994).
Oudet, C., Heilig, R., Hanauer, A. & Mandel, J.-L. Nonradioactive assay for new microsatellite polymorphisms at the 5′ end of the dystrophin gene, and estimation of intragenic recombination. Am. J. hum. Genet. 49, 311–319 (1991).
Oudet, C. et al. Linkage disequilibrium between the fragile X mutation and two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes. Am. J. hum. Genet. 52, 297–304 (1993).
Renges, H.H., Peacock, R., Dunning, A.M., Talmud, P. & Humphries, S.E. Genetic relationship between the 3′-VNTR and diallelic apolipoprotein B gene polymorphisms. Ann. hum. Genet 56, 11–33 (1992).
Martinson, J.J., Boyce, A.J. & Clegg, J.B. VNTR alleles associated with the α-globin locus are haplotype and population related. Am. J. hum. Genet. 55, 513–525 (1994).
Xu, Y., Goodyer, C.G., Deal, C. & Polychronakos, C. Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochemical and Biophysical Research Communications 197, 747–754 (1993).
DeChiara, T.M., Robertson, E.J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859 (1991).
Glannoukakis, N., Deal, C., Paquette, J., Goodyer, C.G. & Polychronakos, C. Parental genomic imprinting of the human IGF2 gene. Nature Genet. 4, 98–101 (1993).
Keller, M.A. et al. Fluorescence-based RT PCR analysis: Determination of the ratio of soluble to membrane-bound forms of FcγRIIA transcripts in hematopoietic cell lines. PCR Meth. Appl. 3, 32–38 (1993).
Falk, C.T. & Rubinstein, P. Haplotype relative risk: an easy reliable way to construct a proper control sample for risk calculations. Ann. hum. Genet. 51, 227–233 (1987).
Thomson, G., Robinson, W.P., Kuhner, M.K., Joe, S. & Klitz, W. HLA and insulin gene associations with IDDM. Genet. Epldemiol. 6, 155–160 (1989).
Owerbach, D., Billesbolle, P., Poulsen, S. & Nerup, J. DNA insertion sequences near the insulin gene affect glucose regulation. Lancet 1, 880–883 (1982).
Permutt, M.A., Rotwein, P., Andreone, T., Ward, W.K. & Porte, D. Islet β-cell function and polymorphism in the 5′-flanking region of the human insulin gene. Diabetes 34, 311–314 (1985).
Coccoza, S. et al. Polymorphism at the 5' end flanking region of the insulin gene is associated with reduced insulin secretion in healthy individuals. Euro. J. clin. Invest. 18, 582–586 (1988).
Weaver, J.U., Kopelman, P.G. & Hitman, G.A. Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flanking region of the human insulin gene. Euro. J. clin. Invest. 22, 265–270 (1992).
Lucassen, A.M. et al. Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype. Hum. molec. Genet, (in the press)
Walker, M.D., Edlund, T., Boulet, A.M. & Rutter, W.J. Cell-specific expression controlled by the 5′-flanking region of insulin and chymotrypsin genes. Nature 306, 557–561 (1983).
Kennedy, G.C., German, M.S. & Rutter, W.J. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nature Genet. 9, 293–298 (1995).
Bartolomei, M.S., Zemel, S. & Tilghman, S.M. Parental imprinting of the mouse H19 gene. Nature 351, 153–155 (1991).
Zhang, Y. & Tycko, B. Monoallelic expression of the human H19 gene. Nature Genet. 1, 40–44 (1992).
Giddings, S.J., King, C.D., Harman, K.W., Flood, J.F. & Carnaghi, L.R. Allele specific inactivation of insulin 1 and 2, in the mouse yolk sac, indicates imprinting. Nature Genet. 6, 310–313 (1994).
Jinno, Y. et al. Mosaic and polymorphic imprinting of the WT1 gene in humans. Nature Genet. 6, 305–309 (1994).
Vu, T.H. & Hoffman, A.R. Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371, 714–717 (1994).
Neumann, B., Kubicka, P. & Barlow, D.P. Characteristics of imprinted genes. Nature Genet. 9, 12–13 (1995).
Green, M. & Krontiris, T.G. Allelic variation of reporter gene activation by the HRAS1 minisatellite. Genomics 17, 429–434 (1993).
Krontiris, T.G., Devlin, B., Karp, D.D., Robert, N.J. & Risch, N. An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. N. Engl. J. Med. 329, 517–523 (1993).
Boam, D.S.W., Clark, A.R. & Docherty, K. Positive and negative regulation of the human insulin gene by multiple transacting factors. J. Biol. Chem. 265, 8285–8296 (1990).
Hammond-Kosack, M.C.U., Dobrinski, B., Lurz, R., Docherty, K. & Kilpatrick, M.W. The human insulin gene linked polymorphic region exhibits an altered DNA structure. Nucleic Acids Res. 20, 231–236 (1992).
Takeda, J., Ishii, S., Seino, Y., Imamato, F. & Imura, H. Negative regulation of human insulin gene expression by the 5′-flanking region in non-pancreatic cells. FEBS Lett. 247, 41–45 (1989).
Royce, N.J., Clarkson, R.E., Wong, Z. & Jeffreys, A. Clustering of hypervariable minisatellites in the proterminal regions of human autosomes. Genomics 3, 352–360 (1988).
Don, R.H., Cox, P.T., Wainwright, B.J., Baker, K. & Mattick, J.S. Touchdown PCR to circumvent spurious priming during gene amplification. Nucleic Acids Res. 19, 4008 (1991).
Reed, P.W. et al. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nature Genet. 7, 390–395 (1994).
Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. hum. Genet. 52, 506–516 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bennett, S., Lucassen, A., Gough, S. et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9, 284–292 (1995). https://doi.org/10.1038/ng0395-284
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0395-284
This article is cited by
-
Identification of key regulatory genes and their working mechanisms in type 1 diabetes
BMC Medical Genomics (2023)
-
Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions
International Journal of Obesity (2023)
-
Association of tyrosine hydroxylase 01 (TH01) microsatellite and insulin gene (INS) variable number of tandem repeat (VNTR) with type 2 diabetes and fasting insulin secretion in Mexican population
Journal of Endocrinological Investigation (2023)
-
100 years of insulin: celebrating the past, present and future of diabetes therapy
Nature Medicine (2021)
-
Large parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects
Nature Communications (2021)