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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, Childhood Arthritis Prospective Study (CAPS)BSPAR study groupChildhood Arthritis Response to Medication Study (CHARMS)Wedderburn LR, Thomson W, Lewis CM, Woo P - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, London, United Kingdom. e.omoyinmi@ucl.ac.uk

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.

Methodology/principal findings: 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.

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Related in: MedlinePlus

Single point results for sJIA, pOJIA, and eOJIA.Point colours indicate the different JIA subtypes. Thresholds are indicated for nominal (p = 0.05) and region-wide significance (p = 0.00166).
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pone-0047673-g001: Single point results for sJIA, pOJIA, and eOJIA.Point colours indicate the different JIA subtypes. Thresholds are indicated for nominal (p = 0.05) and region-wide significance (p = 0.00166).

Mentions: This study of 219 sJIA cases detected significant association at rs1400986, a promoter variant of IL-20 at position −468 (Figure 1) (p = 0.0004; OR = 1.53, 95% CI 1.21–1.93; Table 1). Association at this SNP was previously described by Fife et al [9] in a smaller, but overlapping cohort of sJIA cases. This tSNP gave the strongest single-marker association signal across all SNPs and all JIA subtypes. In the imputation analysis, no SNP exceeded the region-wide p-value for significance (Figure 2; Supplementary Table S1). Penalised logistic regression retained 4 SNPs (all imputed) in the resulting mode (Supplementary Figure S2), although the same evidence for association (log-posterior) was observed for several different groups of retained SNPs (data not shown), indicating that several different choices of SNPs could be used interchangeably.


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, Childhood Arthritis Prospective Study (CAPS)BSPAR study groupChildhood Arthritis Response to Medication Study (CHARMS)Wedderburn LR, Thomson W, Lewis CM, Woo P - PLoS ONE (2012)

Single point results for sJIA, pOJIA, and eOJIA.Point colours indicate the different JIA subtypes. Thresholds are indicated for nominal (p = 0.05) and region-wide significance (p = 0.00166).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475696&req=5

pone-0047673-g001: Single point results for sJIA, pOJIA, and eOJIA.Point colours indicate the different JIA subtypes. Thresholds are indicated for nominal (p = 0.05) and region-wide significance (p = 0.00166).
Mentions: This study of 219 sJIA cases detected significant association at rs1400986, a promoter variant of IL-20 at position −468 (Figure 1) (p = 0.0004; OR = 1.53, 95% CI 1.21–1.93; Table 1). Association at this SNP was previously described by Fife et al [9] in a smaller, but overlapping cohort of sJIA cases. This tSNP gave the strongest single-marker association signal across all SNPs and all JIA subtypes. In the imputation analysis, no SNP exceeded the region-wide p-value for significance (Figure 2; Supplementary Table S1). Penalised logistic regression retained 4 SNPs (all imputed) in the resulting mode (Supplementary Figure S2), although the same evidence for association (log-posterior) was observed for several different groups of retained SNPs (data not shown), indicating that several different choices of SNPs could be used interchangeably.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, London, United Kingdom. e.omoyinmi@ucl.ac.uk

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.

Methodology/principal findings: 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.

Show MeSH
Related in: MedlinePlus