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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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Odds ratios for each haplotype in the best-fitting model for each JIA subtypes, with 95% CI (grey band, with width proportional to haplotype frequency in controls).
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pone-0047673-g004: Odds ratios for each haplotype in the best-fitting model for each JIA subtypes, with 95% CI (grey band, with width proportional to haplotype frequency in controls).

Mentions: In further analysis of the region, we conditioned on rs1400986 and analysed each SNP to detect further signals of association. Decreased evidence for association was observed at many SNPs, but one SNP, rs4129024, remained associated at a suggestive level of significance (Figure 3). After conditioning on both rs1400986 (IL-20) and rs4129024 (MAPKAPK2), no additional tSNP showed suggestive evidence for association. We then examined in more detail the combination of the risk alleles of rs1400986 and rs4129024 tSNPs. The SNP-based model provided the best fitting model (p = 3.2E−5; Table 2), indicating independent contributions to risk from these two SNPs, with no interactions between them. The haplotype of risk alleles [G-T] at rs4129024 and rs1400986 confers an OR of 2.19 for sJIA (95% CI: 1.55–3.10; p = 5.6E−06) compared to the lowest-risk alleles [A-C] (Figure 4); G-T had a frequency of 19% in sJIA cases compared to 12% in WTCCC2 controls.


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)

Odds ratios for each haplotype in the best-fitting model for each JIA subtypes, with 95% CI (grey band, with width proportional to haplotype frequency in controls).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0047673-g004: Odds ratios for each haplotype in the best-fitting model for each JIA subtypes, with 95% CI (grey band, with width proportional to haplotype frequency in controls).
Mentions: In further analysis of the region, we conditioned on rs1400986 and analysed each SNP to detect further signals of association. Decreased evidence for association was observed at many SNPs, but one SNP, rs4129024, remained associated at a suggestive level of significance (Figure 3). After conditioning on both rs1400986 (IL-20) and rs4129024 (MAPKAPK2), no additional tSNP showed suggestive evidence for association. We then examined in more detail the combination of the risk alleles of rs1400986 and rs4129024 tSNPs. The SNP-based model provided the best fitting model (p = 3.2E−5; Table 2), indicating independent contributions to risk from these two SNPs, with no interactions between them. The haplotype of risk alleles [G-T] at rs4129024 and rs1400986 confers an OR of 2.19 for sJIA (95% CI: 1.55–3.10; p = 5.6E−06) compared to the lowest-risk alleles [A-C] (Figure 4); G-T had a frequency of 19% in sJIA cases compared to 12% in WTCCC2 controls.

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