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

The IDDM2 type 1 diabetes susceptibility locus was mapped to(1-6) and identified as(7) 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 69 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) ape dominantly protective(8). 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(9,10). The mode of action of IDDM2 is complicated, however, by parent-of-origin effects(2,7,11-14) and possible allelic heterogeneity within the two defined allele classes(7,15). 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(16). 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.