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. 2010;12(3):R116.
doi: 10.1186/ar3053. Epub 2010 Jun 16.

Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance

Jade E Hollis-Moffatt  1 , Michael Chen-Xu, Ruth Topless, Nicola Dalbeth, Peter J Gow, Andrew A Harrison, John Highton, Peter B B Jones, Michael Nissen, Malcolm D Smith, Andre van Rij, Gregory T Jones, Lisa K Stamp, Tony R Merriman
Affiliations

Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance

Jade E Hollis-Moffatt et al. Arthritis Res Ther. 2010.

Abstract

Introduction: The single nucleotide polymorphism (SNP) rs6822844 within the KIAA1109-TENR-IL2-IL21 gene cluster has been associated with rheumatoid arthritis (RA). Other variants within this cluster, including rs17388568 that is not in linkage disequilibrium (LD) with rs6822844, and rs907715 that is in moderate LD with rs6822844 and rs17388568, have been associated with a number of autoimmune phenotypes, including type 1 diabetes (T1D). Here we aimed to: one, confirm at a genome-wide level of significance association of rs6822844 with RA and, two, evaluate whether or not there were effects independent of rs6822844 on RA at the KIAA1109-TENR-IL2-IL21 locus.

Methods: A total of 842 Australasian RA patients and 1,115 controls of European Caucasian ancestry were genotyped for rs6822844, rs17388568 and rs907715. Meta-analysis of these data with published and publicly-available data was conducted using STATA.

Results: No statistically significant evidence for association was observed in the Australasian sample set for rs6822844 (odds ratio (OR)=0.95 (0.80 to 1.12), P=0.54), or rs17388568 (OR=1.03 (0.90 to 1.19), P=0.65) or rs907715 (OR=0.98 (0.86 to 1.12), P=0.69). When combined in a meta-analysis using data from a total of 9,772 cases and 10,909 controls there was a genome-wide level of significance supporting association of rs6822844 with RA (OR=0.86 (0.82 to 0.91), P=8.8x10(-8), P=2.1x10(-8) including North American Rheumatoid Arthritis Consortium data). Meta-analysis of rs17388568, using a total of 6,585 cases and 7,528 controls, revealed no significant association with RA (OR=1.03, (0.98 to 1.09); P=0.22) and meta-analysis of rs907715 using a total of 2,689 cases and 4,045 controls revealed a trend towards association (OR=0.93 (0.87 to 1.00), P=0.07). However, this trend was not independent of the association at rs6822844.

Conclusions: The KIAA1109-TENR-IL2-IL21 gene cluster, that encodes an interleukin (IL-21) that plays an important role in Th17 cell biology, is the 20th locus for which there is a genome-wide (P<or=5x10(-8)) level of support for association with RA. As for most other autoimmune diseases, with the notable exception of T1D, rs6822844 is the dominant association in the locus. The KIAA1109-TENR-IL2-IL21 locus also confers susceptibility to other autoimmune phenotypes with a heterogeneous pattern of association.

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Figures

Figure 1
Figure 1
Meta-analysis of the KIAA1109-TENR-IL2-IL21 SNP, rs6822844. Combined odds ratio values from data presented in Table 2. There was no evidence for heterogeneity between sample sets (P = 0.25).
Figure 2
Figure 2
Meta-analysis of the KIAA1109-TENR-IL2-IL21 SNP, rs17388568. Combined odds ratio values from the WTCCC [22], Barton et al. [12], and the Australasian case-control sample sets. There was evidence for heterogeneity between sample sets (P = 0.03)
Figure 3
Figure 3
Meta-analysis of the KIAA1109-TENR-IL2-IL21 SNP, rs907715. Combined odds ratio values from WTCCC [22] and the Australasian case-control sample sets. There was no evidence for heterogeneity between sample sets (P = 0.48).
See this image and copyright information in PMC

References

    1. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK, Harley JB. The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis. Rheumatology (Oxford) 2007;46:49–56. doi: 10.1093/rheumatology/kel170. - DOI - PubMed
    1. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW, Wolfe F, Kastner DL, Alfredsson L, Altshuler D, Gregersen PK, Klareskog L, Rioux JD. Replication of putative candidate-gene associations with rheumatoid arthritis in > 4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet. 2005;77:1044–1060. doi: 10.1086/498651. - DOI - PMC - PubMed
    1. Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, Pe'er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M, Barry R, Winslow W, Healy C, Graham RR, Neale BM, Izmailova E, Roubenoff R, Parker AN, Glass R, Karlson EW, Maher N, Hafler DA, Lee DM, Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet. 2007;39:1477–1482. doi: 10.1038/ng.2007.27. - DOI - PMC - PubMed
    1. Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, Donn R, Symmons D, Hider S, Bruce IN. Wellcome Trust Case Control Consortium; Wilson AG, Marinou I, Morgan A, Emery P. YEAR Consortium; Carter A, Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Strachan D, Worthington J. Rheumatoid arthritis association at 6q23. Nat Genet. 2007;39:1431–1433. doi: 10.1038/ng.2007.32. - DOI - PMC - PubMed
    1. Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J, Gibbons L, Plant D. Wellcome Trust Case Control Consortium; Wilson AG, Marinou I, Morgan A, Emery P. YEAR consortium; Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Worthington J. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet. 2008;17:2274–2279. doi: 10.1093/hmg/ddn128. - DOI - PMC - PubMed

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