Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA)

• Published in: PloS one 2012-10, Vol.7 (10), p.e47673-e47673
• Main Authors: Omoyinmi, Ebun, Forabosco, Paola, Hamaoui, Raja, Bryant, Annette, Hinks, Anne, Ursu, Simona, Wedderburn, Lucy R, Thomson, Wendy, Lewis, Cathryn M, Woo, Patricia
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; Arthritis; Arthritis, Juvenile - genetics; Arthritis, Juvenile - pathology; Atherosclerosis; Autoimmune diseases; Biology; Case-Control Studies; Child; Children & youth; Childrens health; Chromosome 1; Chromosomes; Chromosomes, Human, Pair 1; Cytokines; Disease; Epidemiology; Families & family life; Gene expression; Genetic aspects; Genetic diversity; Genetic Loci; Genetic variance; Genomes; Genomics; Haplotypes; Health aspects; Humans; Immunology; Interleukin 10; Interleukin 19; Interleukin 20; Interleukin 24; Interleukin-10 - genetics; Interleukins - genetics; Intracellular Signaling Peptides and Proteins - genetics; Introns; Juvenile arthritis; Linkage Disequilibrium; Medicine; Pathology; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Serine-Threonine Kinases - genetics; Regression Analysis; Rheumatoid arthritis; Rheumatology; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Tagging; Test procedures
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047673

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. 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). 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.