A number of studies have suggested that the INS VNTR may have a biological role in the genetic regulation of insulin expression (70,157,158). The proximity of this polymorphism to the INS transcriptional start site (<400 bp upstream) makes this an attractive hypothesis. Furthermore, an association between VNTR polymorphisms and human disease is not unprecedented. It has been suggested that the human HRAS1 gene, which encodes the H-ras protooncogene and is associated with a genetic susceptibility to certain cancers, is under the allelic effects of a VNTR polymorphism that lies downstream of the gene (159-161). Expansions of nucleotide triplet repeat minisatellites have also been implicated in numerous progressive neurological diseases such as myotonic dystrophy (162). In vitro evidence suggests that these genetic elements may exert a regulatory effect by strengthening nucleosome formation, thereby altering local chromatin structure and, consequently, decreasing the efficiency of transcription from nearby genes (162).
Nevertheless, the exact functional role of the INS variable number tandem repeat (VNTR) is still a subject of discussion (163) and debate in view of conflicting reports as to whether class I VNTR-containing promoter constructs induce are greater (154,157) or lesser (158) insulin gene expression in vitro. In two early reports (154,157), it was asserted that class I-associated insulin expression (associated with diabetes susceptibility) was enhanced as compared with class III insulin gene expression, which is notably considered to be associated with protection from T1DM. In contrast, Kennedy et al. (158) have shown that class III VNTR reporter gene constructs had three time higher reporter gene expression than class I VNTR. Nonetheless, the results from Owerbach and Gabbay (70) do not support those of Kennedy et al. (158). These controversial results raise the concept that methodological differences in conducting the experiments may account for some of these discrepancies. Presently, it remains to be determined how the variant insulin gene expression may influence T1DM susceptibility.
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