
<ArticleTitle>Class III alleles of the variable number of tandem repeat <prot>insulin</prot> polymorphism associated with silencing of thymic <prot>insulin</prot> predispose to type 1 diabetes.</ArticleTitle>
<AbstractText>Type 1 diabetes results from autoimmune destruction of the <prot>insulin</prot>-producing pancreatic beta cells. The <prot>insulin</prot> gene (<prot>INS</prot>) is also expressed in human thymus, an ectopic expression site likely involved in immune tolerance. The IDDM2 diabetes susceptibility locus maps to a minisatellite composed of a variable number of tandem repeats situated 0.5 kb upstream of <prot>INS</prot>. Chromosomes carrying the protective long <prot>INS</prot> variable number of tandem repeats alleles (class III) produce higher levels of thymic <prot>INS</prot> mRNA than those with the predisposing, short class I alleles. However, complete silencing of thymic <prot>INS</prot> transcripts from the class III chromosome was found in a small proportion of heterozygous human thymus samples. We hypothesized that the specific class III alleles found on these chromosomes silence rather than enhance thymic <prot>insulin</prot> expression. To test the prediction that these alleles are predisposing, we developed a DNA fingerprinting method for detecting two putative "silencing" alleles found in two thymus samples (S1, S2). In a set of 287 diabetic children and their parents we found 13 alleles matching the fingerprint of the S1 or S2 alleles. Of 18 possible transmissions, 12 of the S1-S2 alleles were transmitted to the diabetic offspring, a frequency of 0.67, significantly higher than the 0.38 seen in the remaining 142 class III alleles; P = 0.025. This confirms our prediction and represents an additional level of correlation between thymic <prot>insulin</prot> and diabetes susceptibility, which supports a thymic enhancer effect of the <prot>INS</prot> variable number of tandem repeats as the mechanism of <?>IDDM2</?> and refines the contribution of IDDM2 genotyping to diabetes risk assessment.</AbstractText>
