Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele

Abstract

The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

Anomalous behaviour of the 5 ′ insulin gene polymorphism allele 814 : lack of association with Type I diabetes in Basques

“…Ours is the first report presenting differences in contribution to risk of individual class I VNTR alleles in a sample from a relatively homogeneous Caucasian population such as Basques. Although this strict design limits the size of the available population and reduces the probability of detecting differences, our results identify allele 814 as non-predisposing to Type I diabetes and provide additional support for the recently published INS VNTR allele 814 anomalous effect in the disease pathogenesis [3]. The importance of this finding in other populations and its possible role in the mechanism linking IDDM2 and disease are still to be determined, but recent reports have put forward an interesting hypothesis that insulin VNTR allele-mediated control of the level of insulin expression could influence the induction of immune tolerance towards insulin in the thymus [9,10].…”

“…Among the class I alleles that are frequent in Basques, the 42-repeat allele, which corresponds to allele 814, was the only one that was not increased in the diabetic category and its distribution was deviant from the rest of class I alleles (c 2 = 4.14, 1df; p = 0.04), but did not differ significantly from class III alleles, thus suggesting it does not contribute to the risk of development of Type I diabetes. A recent report has also found evidence of the singularity of allele 814 among a large group of Caucasian families of diverse origin with Type I diabetes [3]. Ours is the first report presenting differences in contribution to risk of individual class I VNTR alleles in a sample from a relatively homogeneous Caucasian population such as Basques.…”

“…In Caucasians, the shortest VNTR alleles (class I) are more frequent among patients with Type I diabetes, and long alleles (class III) are associated negatively with the disease. Recent reports have indicated allele specific effects on the risk of the disease [2,3]. Basques are a population living in the western Pyrenees (northern Spain and south-western France) which maintain distinctive genetic characteristics due to the relatively low admixture with other Caucasian populations [4].…”

Genetics of type 1 diabetes mellitus

“…The class I/I homozygous genotype is associated with a twoto five-fold increase in risk of developing T1D, whereas class III alleles seem to provide dominant protection. [93][94][95][96][97][98][99][100][101][102] This susceptibility locus, IDDM2 [MIM 125852], has been mapped to chromosome 11p15.5, and most likely corresponds to the INS VNTR locus, 93 although it has been pointed out that the T1D association extends beyond the 4.1 kb region originally identified 97 towards the tyrosine hydroxylase gene. 103 This is important because subsequent studies including those cited above, which followed this original mapping, presumed that the 4.1 kb was the minimal region-in other words haplotypes were analysed within the 4.1 kb region and not outside it, and eventually provided substantial evidence for the insulin VNTR being the primary locus.…”

Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

“…17,18 Only families with at least one parent homozygous for HLA-DQB1-DQA1-DRB1 haplotypes were included in the study. This resulted in a material consisting of 273 families comprising 147 and 73 parents homozygous for the high-risk haplotypes DQB1*0201-DQA1*0501-DRB1*03 and DQB1*0302-DQA1*03-DRB1*0401, respectively (see Table 1).…”