A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D)(1,2), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to IkappaBalpha and negatively regulates NFkappaB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFkappaB transcriptional activity and similar to2 times greater expression of IL12B, an NFkappaB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.