The concept of pan-autoimmunity susceptibility genes is now firmly established with recent reports of overlap between T1D and Coeliac disease as well as T1D and multiple sclerosis (14
). By targeting variants with suggestive evidence for association with T1D, we have identified a novel association of the AFF3
locus with RA susceptibility. In addition, association of two other loci, the CTLA4
regions, has also been confirmed.
The association of variants in the AFF3
locus with susceptibility to RA has not previously been described. The variant was selected for genotyping because there was suggestive evidence for association with T1D in one large case–control series (P
= 5.0 ×10−6
), although this was not subsequently replicated in a smaller family-based study (8
). However, we have found evidence for association of the variant in three independent case–control series including UK patients with RA and controls with combined analysis reaching a threshold that some regard as achieving genome-wide significance (P
< 5 × 10−7
). The associated variants map to the 5′ and promoter region of the AFF3
gene, which is strongly conserved in evolution and is preferentially expressed in lymphoid cells (16
). It encodes a nuclear factor that can interact with DNA and contains transcriptional activation domains, making it a strong candidate autoimmunity gene.
Our findings also support association of the CTLA4
gene with RA susceptibility. CTLA4 is a co-stimulatory receptor expressed on activated T cells which down-regulates the T cell response. The rs3087243 SNP maps within the 3′ region of the CTLA-4
gene and previous functional studies have identified a correlation between the ratio of soluble to full length CTLA4 mRNA levels with genotype at this variant (17
). Interestingly, the fusion protein, Abatacept (Orencia), a biologic drug with proven efficacy in RA, is a CTLA-4 analogue, highlighting the fact that relatively modest genetic effects may identify targets for treatment which are highly effective in large numbers of patients (18
A region on chromosome 4q27 also showed evidence for association with RA susceptibility in our UK series. The region exhibits substantial linkage disequilibrium encompassing both the IL2 and IL21 genes. Since both are good candidates as autoimmunity susceptibility genes, identifying the causal polymorphism to determine exactly how it predisposes to autoimmune diseases will be challenging.
It is interesting to note that the IL7R
gene showed a trend towards association with RA. The rs6897932 SNP is located in exon 6 and is associated with increased exon skipping resulting in an alteration in the ratio of the membrane-bound to soluble receptor. The IL7 pathway is important in T cell growth and plays a role in regulating cytokine production and, interestingly, expression of IL7R has been correlated with disease activity in peripheral blood mononuclear cells from patients with RA (19
). However, association in other RA data sets is required before this locus can be confidently confirmed as an RA susceptibility gene.
In summary, by targeting loci with prior evidence for association with T1D, we have identified a novel association of AFF3 with RA susceptibility. We have also confirmed association of RA with two other loci (CTLA4 and IL2-21/4q27) so that a total of 13 loci have now been confirmed as associated with RA susceptibility (HLA DRB1, PTPN22, STAT4, TRAF1/C5, 6q23, IL2RB, 12q13, 10p15, CD40, MMEL1, AFF3, 4q27 and CTLA-4). Interestingly, for all but one of these loci (TRAF1/C5), association with other autoimmune diseases, including systemic lupus erythematosus, Graves disease and coeliac disease, has been described, firmly establishing the concept of common susceptibility loci for autoimmunity.