Divergence between genetic determinants of IGF2 transcription levels in leukocytes and of IDDM2-encoded susceptibility to type 1 diabetes.
Vafiadis P., Bennett ST., Todd JA., Grabs R., Polychronakos C.
The IDDM2 susceptibility locus in type 1 diabetes corresponds to a variable number of tandem repeats (VNTR) upstream of the insulin (INS) and insulin-like growth factor 2 (IGF2) genes. Large VNTR alleles (class III) are dominantly protective, whereas small alleles (class I) are predisposing. IGF2 has been considered a prime candidate for mediating IDDM2-encoded susceptibility because of its proximity to the VNTR, mitogenic properties and parental effects at IDDM2 suggest the involvement of an imprinted gene. IGF2 is imprinted with exclusive expression of the paternal gene. However, there is polymorphic relaxation of IGF2 imprinting in leukocytes. VNTR allelic variation affecting either the extent of relaxation or transcription independent of parental origin might explain the IDDM2 effect. To test this, we compared IGF2 expression between chromosomes with a class III or I allele in leukocytes and stimulated lymphocytes. No significant difference was detected between the two classes. Furthermore, the (+) allele of an ApaI polymorphism in the 3'-untranslated region of IGF2 was associated with significantly higher IGF2 messenger ribonucleic acid levels than the (-) allele, but was not associated with type 1 diabetes. The absence of transcriptional effects in leukocytes on IGF2 by the VNTR, which is the disease-predisposing locus, and the presence of a strong association between IGF2 levels and ApaI, which is not associated with the disease, argue against IGF2 expression in leukocytes as the mediator of IDDM2-encoded susceptibility. Taken together, these results support studies suggesting that INS expression in the thymus is a primary target of the IDDM2 susceptibility locus.