Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA).
<h4>Background</h4>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 f...
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oai:doaj.org-article:68848ac2dda2488597842d26489051782021-11-18T08:11:33ZAssociation of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA).1932-620310.1371/journal.pone.0047673https://doaj.org/article/68848ac2dda2488597842d26489051782012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23094074/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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).<h4>Conclusions</h4>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.Ebun OmoyinmiPaola ForaboscoRaja HamaouiAnnette BryantAnne HinksSimona UrsuChildhood Arthritis Prospective Study (CAPS)BSPAR study groupChildhood Arthritis Response to Medication Study (CHARMS)Lucy R WedderburnWendy ThomsonCathryn M LewisPatricia WooPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e47673 (2012) |
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Medicine R Science Q |
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Medicine R Science Q Ebun Omoyinmi Paola Forabosco Raja Hamaoui Annette Bryant Anne Hinks Simona Ursu Childhood Arthritis Prospective Study (CAPS) BSPAR study group Childhood Arthritis Response to Medication Study (CHARMS) Lucy R Wedderburn Wendy Thomson Cathryn M Lewis Patricia Woo Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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).<h4>Conclusions</h4>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. |
| format |
article |
| author |
Ebun Omoyinmi Paola Forabosco Raja Hamaoui Annette Bryant Anne Hinks Simona Ursu Childhood Arthritis Prospective Study (CAPS) BSPAR study group Childhood Arthritis Response to Medication Study (CHARMS) Lucy R Wedderburn Wendy Thomson Cathryn M Lewis Patricia Woo |
| author_facet |
Ebun Omoyinmi Paola Forabosco Raja Hamaoui Annette Bryant Anne Hinks Simona Ursu Childhood Arthritis Prospective Study (CAPS) BSPAR study group Childhood Arthritis Response to Medication Study (CHARMS) Lucy R Wedderburn Wendy Thomson Cathryn M Lewis Patricia Woo |
| author_sort |
Ebun Omoyinmi |
| title |
Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). |
| title_short |
Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). |
| title_full |
Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). |
| title_fullStr |
Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). |
| title_full_unstemmed |
Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). |
| title_sort |
association of the il-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (jia). |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/68848ac2dda2488597842d2648905178 |
| work_keys_str_mv |
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