Here we have combined published studies testing association of two SNPs,
rs6822844 and
rs17388568, located within the KIAA1109
-TENR-IL2-IL21 region with RA: the former with two Dutch [
6,
21], one UK [
12], and one Western Europe sample set [
20]; and the latter with one UK sample set [
12] - along with new Australasian data, and data from the WTCCC [
22]. Meta-analysis (Figure ) showed a consistent protective effect for the minor allele of
rs6822844 with RA (OR = 0.86,
P = 8.8 × 10
-8). A similar protective effect was also observed in the NARAC GWAS for
rs6822844 (OR = 0.84,
P = 0.011), with combined evidence for association with RA of
P = 2.1 × 10
-8 when combined with our meta-analysis
P- value. Our analysis used the same European Caucasian RA sample sets recently meta-analysed by Maita
et al. [
29], with the addition of the WTCCC, Barton
et al. [
12], Australasian and NARAC [
3] data. Meta-analysis of the T1D-associated SNP rs17385868 (Figure ) on the other hand, did not reveal any significant association between the minor allele of
rs17388568 and RA (OR = 1.03,
P = 0.22). Note that SNP rs4505848, in strong LD with
rs17385868, is more strongly associated with T1D (Table ). Whilst there was weak evidence for association at
rs907715 (Table ), in a direction consistent with that previously observed in SLE [
17], this effect appears to be dependent on
rs6822844. When this paper was under review a genome-wide association scan meta-analysis in RA was published, in 5,539 autoantibody positive cases and 20,169 controls of European descent [
30], with
P = 7 × 10
-4 at
rs6822844. We meta-analysed these data with data presented in Table (removing the overlapping WTCCC samples), yielding OR = 0.86 (0.82 to 0.89),
P < 1 × 10
-10. The
rs6822844 data provide compelling evidence supporting a role for the
KIAA1109-TENR-IL2-IL21 locus in etiology of RA in Caucasian populations. Including the HLA region and the 10 loci confirmed by Stahl
et al. [
30] (note that Stahl
et al. did not confirm
KIAA1109-TENR-IL2-IL21 at a genome-wide level of significance),
KIAA1109-TENR-IL2-IL21 is the 20
th locus associated with RA at a genome-wide level of significance (
P ≤ 5 × 10
-8). The association at
rs6822844 dominates at this locus, with no evidence for an independent effect at
rs17385868, as is seen in T1D (Table ) [
13].
The
KIAA1109-TENR-IL2-IL21 region was first implicated in autoimmunity after a GWAS in T1D [
13,
22] and has since been associated, also with a genome-wide level of support, with celiac disease [
16] and ulcerative colitis [
14] and, with lower supporting evidence, with SLE, psoriatic arthritis, Graves' disease and juvenile idiopathic arthritis [
13,
17-
19] (Table ). The region is characterized by a high degree of linkage disequilibrium [
13], meaning that the underlying disease-causing variant(s) and gene(s) have not yet been determined. Collectively, these data point to at least two independent associations within the
KIAA1109-TENR-IL2-IL21 region, with the pattern of association differing between autoimmune phenotypes (Table ); one marked by
rs17388568 (in the TENR gene) and the other by
rs6822844 (which maps between IL-2 and IL-21). There is no appreciable linkage disequilibrium between
rs17388568 and
rs6822844 (r
2 = 0.07 in HapMap CEU samples). Different patterns of association are evident in the different autoimmune phenotypes. For example (referring to the risk conferred by the minor allele), susceptibility at
rs17388568 and protection at
rs6822844 is observed in T1D [
13,
21], some evidence for protection is seen at
rs17388568 in Graves' disease [
13], there is no evidence for association of
rs17388568 (or markers in high LD) with RA (Figure ) whereas
rs6822844 confers protection (Table ). The studies in Crohn's disease, ulcerative colitis, celiac disease, psoriatic arthritis, and JIA are consistent in reporting the
rs6822844-mediated minor allele protective effect [
14-
16,
18,
19] (Table ), with little data available on
rs17388568 in comparison to
rs6822844. The single study in SLE [
17] did not include SNPs in LD with
rs6822844, however there was evidence for a susceptibility effect at
rs17388568 (using
rs2221903 which is in strong LD with
rs17388568, Table ). Collectively, these studies point to heterogeneity at
rs17388568 between RA and other autoimmune phenotypes (T1D, GD, SLE) with which RA shares other genes and clinical features.
Within the
KIAA1109-TENR-IL2-IL21 gene cluster, IL-21 is of particular interest in the context of RA, and the Th1/Th17 axis in which IL-23R is involved. IL-21 is required for differentiation of naïve human CD4
+ T cells into Th17 cells [
31], whereas IL-23 is critical in the expansion and maintenance of Th17 cells [
32,
33]. It is important to note that Th17 cells produce a variety of cytokines including IL-17A, IL-17F, IL-21 and IL-22. Human studies have demonstrated that IL-21 receptor (IL-21R)-positive cells are significantly increased in inflamed synovial tissues of RA patients compared to controls and that IL-21 enhances local T-cell activation, proliferation and proinflammatory cytokine secretion [
34,
35]. Alongside these findings, animal studies demonstrate that IL-21R deficient mice have normal T-cell and NK cell development but fail to develop spontaneous autoimmune disease suggesting that IL-21 plays a vital role in the development of autoimmune disease in rodents. Studies using arthritic mice and rats also demonstrate that inhibition of IL-21 expression correlates with modulation of serum IL-6 levels and improvements in disease severity [
36]. However, it remains to be determined whether inhibition of IL-21 in humans with RA will have a similar beneficial effect given the significant differences between Th17 cell biology in mice and men.
Given the importance of Th17 cells in autoimmunity [
37], the differential genetic effects observed in various autoimmune phenotypes mediated by the
IL23R and
KIAA1109-TENR-IL2-IL21 regions, evidence for genetic interaction between the
KIAA1109-TENR-IL2-IL21 region and
IL23R (in ulcerative colitis at least) [
38], there are reasonable grounds for considering the hypothesis that genetic control of the Th1/Th17 axis is centered on cytokines (and their receptors) important in Th17 biology. It is important to note that not all RA patients have evidence of IL-17A within synovial tissue [
39] and the role of IL-17A appears to be as an amplifier of inflammation rather than an absolute requirement for inflammation in RA. One possible explanation is genetic variation in the
KIAA1109-TENR-IL2-IL21 locus that results in non-functional IL-21 and hence lack of IL-17A or vice versa. Regulation of this axis may be an important factor in determining the risk to particular autoimmune phenotypes, which may have implications for selection of targeted biological therapies within an individual. What will be important in understanding molecular control of autoimmunity will be association studies in large sample sets from different autoimmune phenotypes that comprehensively capture common variation in the
IL23R and
KIAA1109-TENR-IL2-IL21 loci, fine-mapping of the genetic effects and analysis of interaction between the disease-associated variants, both within and between loci.
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