title: Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA).
abstract: BACKGROUND
  The cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations.
  
  
  RESULTS
  Fifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21-1.93; p = 0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p = 0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p = 3.2E-5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3'UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003).
  
  
  CONCLUSIONS
  This study supports previous association of IL-20 with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.
authors.affiliation: Department of Immunology and Molecular Pathology, University College London, London, United Kingdom. e.omoyinmi@ucl.ac.uk
authors.forename: Ebun
authors.initials: E
authors.lastname: Omoyinmi
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
authors.forename: Raja
authors.initials: R
authors.lastname: Hamaoui
authors.forename: Annette
authors.initials: A
authors.lastname: Bryant
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.forename: Simona
authors.initials: S
authors.lastname: Ursu
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
mesh_terms: D001171:Arthritis, Juvenile / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002878:Chromosomes, Human, Pair 1; D056426:Genetic Loci; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007438:Introns; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012044:Regression Analysis; D000099190:MAP-Kinase-Activated Kinase 2; D000099180:Interleukin-24
chemical_list: D016753:Interleukin-10; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; D000099180:Interleukin-24; C421250:IL19 protein, human; C422042:interleukin 20