Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1 D)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 T1 D 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 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 NFKB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.
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