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 × 10 −7 ). SUMO4 conjugates to IκBα and negatively regulates NFκB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFκB transcriptional activity and ∼2 times greater expression of IL12B , an NFκB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.