title: IL-10R polymorphisms are associated with very-early-onset ulcerative colitis.
abstract: BACKGROUND
  Interleukin-10 (IL-10) signaling genes are attractive inflammatory bowel disease (IBD) candidate genes as IL-10 restricts intestinal inflammation, IL-10 polymorphisms have been associated with IBD in genome-wide association studies, and mutations in IL-10 and IL-10 receptor (IL-10R) genes have been reported in immunodeficient children with severe infantile-onset IBD. Our objective was to determine if IL-10R polymorphisms were associated with early-onset IBD (EO-IBD) and very-early-onset IBD (VEO-IBD).
  
  
  METHODS
  Candidate-gene analysis of IL10RA and IL10RB was performed after initial sequencing of an infantile onset-IBD patient identified a novel homozygous mutation. The discovery cohort included 188 EO-IBD subjects and 188 healthy subjects. Polymorphisms associated with IBD in the discovery cohort were genotyped in an independent validation cohort of 422 EO-IBD subjects and 480 healthy subjects.
  
  
  RESULTS
  We identified a homozygous, splice-site point mutation in IL10RA in an infantile-onset IBD patient causing a premature stop codon (P206X) and IL-10 insensitivity. IL10RA and IL10RB sequencing in the discovery cohort identified five IL10RA polymorphisms associated with ulcerative colitis (UC) and two IL10RB polymorphisms associated with Crohn's disease (CD). Of these polymorphisms, two IL10RA single nucleotide polymorphisms, rs2228054 and rs2228055, were associated with VEO-UC in the discovery cohort and replicated in an independent validation cohort (odds ratio [OR] 3.08, combined P = 2 x 10(-4); and OR 2.93, P = 6 x 10(-4), respectively).
  
  
  CONCLUSIONS
  We identified IL10RA polymorphisms that confer risk for developing VEO-UC. Additionally, we identified the first splice site mutation in IL10RA resulting in infantile-onset IBD. This study expands the phenotype of IL10RA polymorphisms to include both severe arthritis and VEO-UC.
authors.affiliation: Division of Pediatric Gastroenterology, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moran
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Walters
authors.forename: Cong-Hui
authors.initials: CH
authors.lastname: Guo
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Dan
authors.initials: D
authors.lastname: Turner
authors.forename: Victorien M
authors.initials: VM
authors.lastname: Wolters
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bandsma
authors.forename: Marialena
authors.initials: M
authors.lastname: Mouzaki
authors.forename: Mary
authors.initials: M
authors.lastname: Zachos
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Langer
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Benseler
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics*; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D022821:RNA Splice Sites / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C081846:IL10RB protein, human; D053709:Interleukin-10 Receptor alpha Subunit; D053710:Interleukin-10 Receptor beta Subunit; D022821:RNA Splice Sites; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10