title: A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.
abstract: Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), 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 I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, Georgia 30912, USA.
authors.forename: Dehuang
authors.initials: D
authors.lastname: Guo
authors.forename: Manyu
authors.initials: M
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Sarah
authors.initials: S
authors.lastname: Eckenrode
authors.forename: Diane
authors.initials: D
authors.lastname: Hopkins
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zheng
authors.forename: Sharad
authors.initials: S
authors.lastname: Purohit
authors.forename: Robert H
authors.initials: RH
authors.lastname: Podolsky
authors.forename: Andrew
authors.initials: A
authors.lastname: Muir
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Todd
authors.initials: T
authors.lastname: Brusko
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Paolo
authors.initials: P
authors.lastname: Pozzilli
authors.forename: Adina
authors.initials: A
authors.lastname: Zeidler
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Raffel
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.forename: Yongsoo
authors.initials: Y
authors.lastname: Park
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano-Rios
authors.forename: Maria T Martinez
authors.initials: MT
authors.lastname: Larrad
authors.forename: Zixin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Henri-Jean
authors.initials: HJ
authors.lastname: Garchon
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Bach
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: C489647:SUMO4 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins