title: Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease.
abstract: Genome-wide association studies have implicated common variation at the 20q13 locus in inflammatory bowel disease, particularly for the pediatric Crohn's form. This locus harbors tumor necrosis factor receptor superfamily (TNFRSF6B), encoding a secreted protein, decoy receptor 3 (DcR3), which binds to and neutralizes pro-inflammatory cytokines of the tumor necrosis factor superfamily. We sought to further the evidence of DcR3's role in pediatric IBD by identifying missense mutations with functional significance within TNFRSF6B. We sequenced the exons of the gene in 528 Caucasian pediatric IBD cases and 549 Caucasian healthy controls to establish the frequency of such events in each population. Sequencing revealed that our IBD cohort harbored a greater number of missense variants, yielding an odds ratio of 3.9 (P-value=0.005). Using functional assays, we established that the frequency of mutants defective in secretion from cultured cells was greater in the Crohn's category than in the controls, yielding an odds ratio of 7.1 (P-value=0.004). These results suggest that rare defective variants in TNFRSF6B have a role in the pathogenesis of some cases of IBD and that interventions targeting this group of tumor necrosis factor-family members may benefit patients with IBD.
authors: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: C J
authors: CJ
authors: Cardinale
authors: Z
authors: Z
authors: Wei
authors: S
authors: S
authors: Panossian
authors: F
authors: F
authors: Wang
authors: C E
authors: CE
authors: Kim
authors: F D
authors: FD
authors: Mentch
authors: R M
authors: RM
authors: Chiavacci
authors: K E
authors: KE
authors: Kachelries
authors: R
authors: R
authors: Pandey
authors: S F A
authors: SF
authors: Grant
authors: R N
authors: RN
authors: Baldassano
authors: H
authors: H
authors: Hakonarson
mesh_terms: D000293:Adolescent; D001741:Black or African American; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000208:ethnology / Q000235:genetics*; D003424:Crohn Disease / Q000208:ethnology / Q000235:genetics*; D005089:Exocytosis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D044465:White People
chemical_list: D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human