Endocrine Abstracts

Graves' disease and type 1 diabetes frequently occur together and this would suggest that genetic susceptibility is due to common loci. The insulin (INS) gene region (IDDM2) on chromosome 11p15.5 is linked to, and associated with, type 1 diabetes and it has been suggested that it may be acting as a general autoimmunity locus. Susceptibility is conferred by the variable number of tandem repeats (VNTR); a polymorphic region situated 5' to the INS gene. The class I/I homozygote genotype is strongly associated with type 1 diabetes and the class I allele is in linkage disequilibrium with the A allele of a single nucleotide polymorphism (SNP), identified by the restriction enzyme Hph1. Using the Hph1 SNP of the INS gene locus, we performed an association study using family and case-control data sets of patients with Graves' disease. Genomic DNA from 610 Graves' index cases, 600 controls and 212 simplex families of British white Caucasian origin was amplified using polymerase chain reaction (PCR) and Hph1 enzyme was used to digest the product. Three fragments resulted, 240 bp and 160 bp in those who were homozygous positive for the polymorphism (AA), 280, 240 and 160 bp in heterozygotes (AB), 280 and 160 bp in homozygote negative individuals (BB). Using the Chi squared test no significant differences in genotype frequencies were found between the Graves' cases and controls (Chi = 0.15, p = 0.703). The Transmission Disequilibrium Test (TDT) was used to analyse the data from the family data set. 76 families were informative for TDT analysis and there was no evidence of preferential transmission of the A allele to affected offspring (47 transmissions, 40 nontransmissions). The 2x2 test of heterogeneity comparing transmissions between affected and unaffected siblings showed no difference (Chi = 0.025, p = 0.876). These data suggest that the INS VNTR is not a susceptibility locus for Graves' disease in the UK.