Human type 1 diabetes and the insulin gene: principles of mapping polygenes

Annu Rev Genet. 1996;30:343-70. doi: 10.1146/annurev.genet.30.1.343.


We review the strategy used to identify a susceptibility locus (IDDM2) for type 1 (insulin dependent) diabetes mellitus. As type 1 diabetes is becoming the paradigm for dissecting multifactorial disease genetics, the approach described provides important general guidelines for positional cloning of human disease polygenes. Main topics include: (a) historical conspectus of the mapping and identification of IDDM2--a critical survey of the work leading up to the conclusion that IDDM2 most likely corresponds to allelic variation at the insulin gene minisatellite (VNTR) locus; (b) the nature of allelic (length and sequence) variation at the VNTR locus; (c) gene interactions and disease pathogenesis; (d) mechanism of action of the INS VNTR in type 1 diabetes--insulin gene expression, parent-of-origin effects (genomic imprinting); and (e) summary and future prospects--alleles of the insulin VNTR that are protective for type 1 diabetes appear to encode susceptibility to type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alleles
  • Chromosome Mapping*
  • Diabetes Mellitus, Type 1 / genetics*
  • Genetic Variation
  • Genomic Imprinting
  • Humans
  • Minisatellite Repeats