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

Bryant, A

BSPAR study group,

Childhood Arthritis Prospective Study (CAPS),

Childhood Arthritis Response to Medication Study (CHARMS),

Forabosco, P

Hamaoui, R

Hinks, A

Lewis, CM

Omoyinmi, E

Thomson, W

Ursu, S

Wedderburn, LR

Woo, P

PLoS ONE

English

PubMed

Childhood Arthritis Prospective Study (CAPS)

BSPAR study group

Childhood Arthritis Response to Medication Study (CHARMS)

UCL Discovery

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

BackgroundThe 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.Methodology/Principal FindingsFifty-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).ConclusionsThis 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

Omoyinmi, Ebun

Forabosco, Paola

Hamaoui, Raja

Bryant, Annette

Hinks, Anne

Ursu, Simona

Wedderburn, Lucy R

Thomson, Wendy

Lewis, Cathryn M

Woo, Patricia

King's Research Portal

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

<div><h3>Background</h3><p>The cytokine <em>IL-10</em> and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in <em>IL-10</em> 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 <em>IL-10</em> 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.</p> <h3>Methodology/Principal Findings</h3><p>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 <em>IL-20</em> (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 <em>IL-20</em> and <em>IL-24</em>, including a rare, functional, missense variant at <em>IL-24</em> 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 <em>MAPKAPK2</em> (p = 3.2E−5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of <em>IL-10</em> showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3′UTR of <em>FCAMR</em>) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003).</p> <h3>Conclusions</h3><p>This study supports previous association of <em>IL-20</em> 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.</p> </div

Ebun Omoyinmi (125984)

Paola Forabosco (125986)

Raja Hamaoui (125988)

Annette Bryant (125990)

Anne Hinks (23498)

Simona Ursu (125994)

Lucy R. Wedderburn (125999)

Wendy Thomson (68038)

Cathryn M. Lewis (126002)

Patricia Woo (60657)

FigShare

Association of the <em>IL-10</em> Gene Family Locus on Chromosome 1 with Juvenile Idiopathic Arthritis (JIA)

 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.) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003). 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

Omoyinmi Ebun

Forabosco Paola

Hamaoui Raja

Bryant Annette

Hinks Anne

Ursu Simona

Wedderburn Lucy R.

Thomson Wendy

Lewis Cathryn M.

Woo Patricia

Public Library of Science (PLOS)

 Gene Family Locus on Chromosome 1 with Juvenile Idiopathic Arthritis (JIA)

BackgroundThe 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.Methodology/principal findingsFifty-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).ConclusionsThis 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 Omoyinmi

Paola Forabosco

Raja Hamaoui

Annette Bryant

Anne Hinks

Simona Ursu

Lucy R Wedderburn

Wendy Thomson

Cathryn M Lewis

Patricia Woo

Directory of Open Access Journals

Lucy R. Wedderburn

Cathryn M. Lewis

null null

Crossref

Association of the IL-10 Gene Family Locus on Chromosome 1 with Juvenile Idiopathic Arthritis (JIA)

Omoyinmi, E.

Forabosco, P.

Hamaoui, R.

Bryant, A.

Hinks, A.

Ursu, S.

Wedderburn, L.R.

Thomson, W.

Lewis, C.M.

Woo, P.

Gardner-Medwin, J.

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https://figshare.com/articles/Association_of_the_IL_10_Gene_Family_Locus_on_Chromosome_1_with_Juvenile_Idiopathic_Arthritis_JIA_/118290

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

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