Polymorphism in the 5′ Flanking Region of the Human Insulin Gene: A Genetic Marker for Non-Insulin-Dependent Diabetes

We sought to determine whether differences in the human insulin gene or its immediate flanking sequences could be found in diabetes. Peripheral leukocyte DNA from 217 unrelated persons, including blacks, whites, and Pima Indians, was analyzed by restriction-enzyme digestion, blotting to nitrocellulose filters, and hybridization to cloned [ 32 P]insulin-gene probes. A region of length variation including deletions (0.1 to 0.2 kilo-base pairs) or insertions (0.6 to 5.5 kb) of DNA was found only in the immediate 5′ flanking region in 33 per cent of the genes examined. A 1.6-kb insertion accounted for 80 per cent of the polymorphism. This variant was found more often in subjects with non-insulin-dependent diabetes than in nondiabetics, regardless of race (P = 0.011). Length polymorphism in the 5′ flanking region of the insulin gene may provide a genetic marker for non-insulin-dependent diabetes. (N Engl J Med. 1983; 308:65–71.) THE genetics of diabetes remains an area of controversy and speculation. Glucose intolerance, which may result from a number of different patho-physiologic mechanisms, 1 continues to be the only diagnostic criterion. Diabetes genetics is further complicated by variation in age at onset. The recent division of diabetes into insulin-dependent and non-insulin-dependent types emphasizes the requirement of insulin rather than age at diagnosis. 2 In insulin-dependent diabetes an absolute lack of insulin may be a consequence of immune-mediated beta-cell destruction. 3 HLA haplotypes DR3 and DR4 are highly associated with this disorder and are presumably linked to a diabetes-susceptibility locus on chromosome 6. 4 In . . .