A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes.

Abstract

Genetic studies have identified a number of loci demonstrating linkage to type 1 diabetes. One of the largest single contributors to genetic susceptibility, after the major histocompatability complex, is the IDDM2 locus, which maps to a nontranscribed variable number of tandem repeats (VNTR) minisatellite upstream of the insulin (INS) and insulin-like growth factor 2 (IGF2) genes. In a progression from population to functional studies, recent reports have shown that VNTR susceptibility alleles (class I) have different transcriptional effects on INS than protective VNTR alleles (class III) in thymus and pancreas, two tissues important in the pathogenesis of the disease. Similar VNTR transcriptional effects on IGF2 have also been proposed as a mechanism by which the IDDM2 locus confers susceptibility in addition to, or instead of, effects on INS. We evaluated this hypothesis by comparing IGF2 expression levels from chromosomes with the protective class III alleles to those with class I alleles in tissues relevant to type 1 diabetes pathogenesis. In thymus, class III alleles were associated with an IGF2 mRNA level of 4.7 +/- 0.9 (mean +/- SE, arbitrary units, n = 12) compared with 4.7 +/- 1.3 for class I alleles (n = 17). The same absence of a significant difference was found in pancreas, where class III alleles were associated with a level of 28.4 +/- 4.2 (n = 7) and class I alleles with a level of 29.5 +/- 5.2 (n = 6). There was a significant correlation between fetal age and IGF2 in both tissues, but fetal ages were not different in the genotype groups compared. We therefore did not detect any significant difference in IGF2 mRNA levels associated with the protective class of VNTR alleles as compared with the predisposing class. This is evidence against the hypotheses that have suggested IGF2 is a mediator of IDDM2-encoded susceptibility and corroborates previous studies suggesting insulin is the gene involved.

Genes Mediating Environment Interactions in Type 1 Diabetes

“…Paquette et al [58] found an association between class I alleles of the INS promoter VNTR and increased expression of IGF2 in placenta, and it has been suggested that IGF2 expression may have some effect on intrauterine growth and birth size, both of which are known T1D risk factors [59]. However, this finding has not been confirmed in other studies [60,61].…”

Associations of IGF2 ApaI RFLP and INS VNTR class I allele size with obesity

“…However, Vafiadis et al 31 found the IGF2 ApaI G allele (associated with increased BMI in our studies) was associated with significantly higher IGF2 mRNA levels than the A allele, but unlike Paquette et al in placenta and liver cells, found no difference in expression of leukocyte IGF2 with respect to INS VNTR class I/III genotype, as they had previously established in thymus and pancreas. 32 Since our results show no association between INS VNTR I vs III classification and BMI, but substantial association with class I small subclass alleles (in coupling with IGF2 ApaI A alleles) versus large subclass alleles (in coupling with IGF2 ApaI G alleles), a precise aetiological chain between IGF2 and INS mRNA and hormone expression and protection from obesity (the IGF2 ApaI A/INS VNTR class I small subclass haplotype) cannot yet be inferred, although its genetic susceptibility is already measurable. The most plausible hypothesis may be that there is increased average transcription and IGF-II secretion from liver.…”

IGF-I mRNA and Signaling in the Diabetic Retina

“…Because the accuracy of competitor concentration may not be absolute, the data are presented as transcriptto-housekeeping ratio. The linearity of the PCRs and the appropriate concentration of competitors to be used were determined as described by Vafiadis et al (23). Immunoblotting and immunoprecipitation.…”