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.
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We thank R.T. Hay for the NFκB-dependent luciferase reporter (3enh conA luc) and IκBα expression construct, R. McIndoe for suggestions about this project and J. Gu for discussion of manuscript preparation. This study was supported in part by grants from the Combined Intramural Grants Program, the Juvenile Diabetes Research Foundation (C.Y.W.) and the National Institute of Child Health and Development (J.X.S.).
The authors declare no competing financial interests.
LD of SNPs flanking the IDDM5 interval. (PDF 92 kb)
Pooled DNA sequencing results for the M55V of SUMO4. (PDF 103 kb)
Semi-quantitative Western analysis of IL-p40 in stimulated/unstimulated PBMC lysates from individuals studied in Figure 4. (PDF 123 kb)
Case-control association results for 001Msp. (PDF 53 kb)
Family-based association results for 001Msp. (PDF 90 kb)
Family-based association results for 268Hha. (PDF 89 kb)
Family-based association results for 012Taq. (PDF 89 kb)
Case-control association results for M55V. (PDF 44 kb)
Family-based association results for M55V. (PDF 89 kb)
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