The insulin gene locus has been studied in a large kindred with maturity-onset diabetes of the young (MODY) characterized by hypoinsulinemia. DNA was isolated from peripheral leukocytes of 42 family members and 5 spouses. A highly polymorphic region in the 5'-flanking portion of the human insulin gene provided an opportunity for linkage analysis. The presence of three different length polymorphisms of +1600 base pairs (bp), −50 bp, and −150 bp different from the common size allele allowed haplotype assignment of insulin alleles. The hypothesis of linkage was tested by calculating the log of the ratio of the likelihood of the hypothesis of linkage to that of the hypothesis of nonlinkage (LOD score) at a given recombination distance between the insulin polymorphism and the diabetes locus. At a recombination frequency of 0.0, the LOD score was −14.50 and, therefore, the hypothesis of tight linkage can be strongly rejected.

This report is the third study of the relationship between the insulin locus and MODY; however, it is the first report in which a formal linkage analysis indicates with a high degree of probability no linkage between the insulin locus and hypoinsulinemia in a family. Because MODY is a heterogeneous disorder, it may be that different genotypes result in a composite phenotype. The lack of linkage between an insulin allele and MODY in a total of four families studied, however, suggests that the insulin locus is probably not a marker for the MODY phenotype. These results do not exclude the possibility that the insulin locus may be involved in the etiology of other forms of NIDDM.

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