Population studies have suggested an increased frequency of small DNA insertions (class 1 alleles) 5' to the insulin gene in IDDM. The present study was undertaken to examine this relationship within families. 27 families with at least one IDDM offspring were studied. Analysis of the insulin gene polymorphism was performed by digestion of DNA with Bgl I, Sst I, Rsa I, or Pvu II and hybridization with either a 32-P-labelled insulin gene probe or polymorphic region-specific probe. An increased frequency of matings between two individuals homozygous for small inserts (genotype 1/1) was found among the parents of diabetics (p<.04), as well as an increased frequency of the 1/1 individuals within the entire sample, and increased total frequency of 1 alleles (p<.055). This increased frequency was present in nondiabetic siblings as well (p<.05). These results show that ascertainment through an offspring with IDDM selects for families with high frequencies of homozygosity for small inserts and thus suggest that the insulin gene polymorphism is providing part of the genetic predisposition to IDDM. When the major portion of genetic predisposition is provided by other genes (HLA accounts for 60-70% in IDDM), identification of additional susceptibility genes becomes difficult. Even when formal linkage analysis is uninformative, our studies indicate that analysis for aggregation of specific alleles within families is a useful approach to this problem.
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Raffel, L., Hitman, G., Bell, G. et al. 849 THE INSULIN GENE POLYMORPHISM IN TYPE I DIABETES (IDDM) FAMILIES. Pediatr Res 19, 252 (1985). https://doi.org/10.1203/00006450-198504000-00879