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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  = 8.8 × 10 -8 ,  P  = 2.1 × 10 -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 20 th  locus for which there is a genome-wide ( P  ≤ 5 ×10 -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.

arthritis research and therapy

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