Abstract
Insulin-dependent diabetes mellitus (IDDM) is characterized by autoimmune destruction of the insulin secreting β-cells of the pancreas and subsequent disruption of glucose metabolism. The tendency of IDDM to cluster in families and the modest (36%) concordance rate in monozygotic twins indicates that both genetic and environmental factors contribute to IDDM susceptibility1. Recent genome-wide searches using the affected sib-pair (ASP) approach have provided evidence for novel loci, in addition to HLA(IDDM1) and insulin (IDDM2), which show evidence of linkage to IDDM (P<0.05)3–4. We have evaluated 35 microsatellite marker loci on human chromosome 7 for linkage to IDDM in 339 affected sib-pair families. Increased sharing of parental haplotypes in affected sib-pairs was detected for two microsatellite markers flanking glucokinase (GCK). Preferential transmission of alleles to affected offspring was observed at one of these marker loci, GCK3, indicating linkage disequilibrium between the marker and a disease susceptibility locus. This combination of linkage and disease association suggests that glucokinase, or a gene in the vicinity, plays an important part in IDDM susceptibility.
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References
Olmos, P. et al. The significance of the concordance rate for type 1 (insulin-dependent) diabetes in identical twins. Diabetologia 31, 747–750 (1988).
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. & Tobias, T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 8, 189–193 (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).
Bain, S.C., Barnett, A.H. & Todd, J.A. Lack of association between type 1 diabetes and the glucokinase gene. Lancet 340, 54–55 (1992).
Stoffel, M. et al. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. Proc. natn. Acad. Scl. U.S.A. 89, 7698–7702 (1992).
Risch, N. Assessing the role of HLA-linked and unlinked determinants of disease. Am. J. hum. Genet. 40, 1–14 (1987).
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).
Julier, C. et al. lnsulin-IGF2 region on chromsome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155–159 (1991).
Bennett, S.T. et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature Genet. 9, 284–292 (1995).
Kennedy, G.C., German, M.S. & Putter, W.J. The minisatellite in the diabetes susceptibility locus IDDM2regulates insulin transcription. Nature Gen. 9, 293–298 (1995).
Don, R.H.P.T., Wainwright, B.J., Baker, K. & Mattick, S. ‘Touchdown’ PCR to circumvent spurious priming during gene amplification. Nucl. Acids Res. 10, 4008 (1991).
Charmley, P. & Concannon, P. Polymorphism and phylogeny of dinucleotide repeats in human T-cell receptor Vb6 genes. Immunogenetics 38, 92–97 (1993).
Stoffel, M. & Bell, G.I. Characterization of a third simple tandem repeat polymorphism in the human glucokinase gene. Diabetologia 36, 170–171 (1993).
Lange, K., Weeks, D.E. & Boehnke, M. Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE Genet Epidemiol. 5, 471–472 (1988).
Kretz, K.A., Carson, G.S. & Brien, J.S. Direct sequencing from low-melt agarose with Sequenase. Nucl. Acids Res. 17, 5864 (1989).
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Rowe, R., Wapelhorst, B., Bell, G. et al. Linkage and association between insulin–dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7. Nat Genet 10, 240–242 (1995). https://doi.org/10.1038/ng0695-240
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DOI: https://doi.org/10.1038/ng0695-240
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