Pedigree analysis of the 5′ flanking region of the insulin gene in familial diabetes mellitus

Non-insulin-dependent diabetes mellitus (NIDDM) has been reported to be associated with an insertion polymorphism in the 5′ flanking region of the human insulin gene. We have attempted to examine linkage of this polymorphism to the phenotype of NIDDM by studying multiple pedigrees. We evaluated 142 individuals (120 white, 22 black), 80 of whom were from 7 pedigrees (5 white, 2 black) ranging in size from 4 to 37 members. Of these, 52 subjects had NIDDM, 10 had insulin-dependent diabetes mellitus (IDDM), and 80 were nondiabetics (ND). DNA was extracted from leukocytes and after digestion with Sst I, and electrophoresis, the DNA was blotted to nitrocellulose filters and hybridized to a α³²P-labeled insulin gene probe. Two alleles of 6.0 and 7.6 kb in size were detected, the latter corresponding to the common previously described insertion polymorphism. In these families, the 7.6 kb allele occurred in 32 of 57 ND, 3 of 5 IDDM, and 10 of 18 NIDDM (P = 0.98). When sibships were analyzed the 7.6 kb allele occurred in 6 of 13 ND, 3 of 5 IDDM, and 8 of 12 NIDDM (P = 0.58). In examining 72 unrelated subjects, including 12 spouses from the pedigrees, the 7.6 kb allele was documented in 16 of 36 ND, 1 of 5 IDDM, and 16 of 31 NIDDM (P = 0.59). In these individuals and in the multiple families studied the insertion polymorphism flanking the insulin gene showed Mendelian inheritance and assorted independently of the phenotype of diabetes mellitus.