Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease

Rheumatoid arthritis (RA) is an auto-immune, inflammatory joint condition, affecting 0.8% of the UK population [1]. It has long been established that the major genetic predisposition to this disease is contributed by variants of the class II HLA gene, HLA DRB1. Both type 1 diabetes (T1D) and coeliac disease (CeD) are also auto-immune, inflammatory diseases for which the major genetic contribution arises from the major histocompatibility complex and which are also characterised by autoantibody formation [2].

Recent genome wide association and subsequent replication studies in these three diseases have revealed a large number of well validated, non-HLA genetic risk loci providing an opportunity to explore the possibility of overlapping susceptibility between them [3]. Testing confirmed T1D susceptibility loci in CeD samples has already resulted in the identification of novel CeD loci [2]. A previous study exploring the overlap of CeD and RA susceptibility loci identified association to six regions [4]. We have recently reported our findings of the testing of putative T1D susceptibility loci in RA, which identified AFF3 as a novel RA susceptibility locus [5]. However, exploring the overlap between the three diseases in more detail may provide a further opportunity to elucidate the genetic similarities, and differences, between these common autoimmune diseases.

We, therefore, tested 14 validated susceptibility loci from CeD and T1D in a large, well powered cohort of British Caucasian patients with RA and independent controls to explore the overlap between loci identified in all three conditions.

By investigating the genetic overlap of CeD genes with RA, we have identified the TAGAP locus as being associated with RA. Our findings confirm and refine the results of a previous study in RA that also showed association to the TAGAP region but with a different variant; our results show that the same SNP that is associated with CeD and T1D also shows stronger evidence for association with RA [11]. Data from the current study extend that of previous work identifying that CTLA-4, the IL2_21 region, 6q23 (TNFAIP3), SH2B3, PRKCQ, MMEL1 and now TAGAP are susceptibility loci that are common to the three autoimmune diseases examined in the current study: T1D, CeD and RA [2, 5].

The current study is limited by the fact that, because the identification of novel susceptibility markers is progressing rapidly, a number of additional CeD and T1D susceptibility loci have been identified more recently, which have not been tested as yet for association with RA [12‐14]. Hence, this is not a comprehensive examination of the overlap among all T1D, CeD and RA loci. However, of the loci tested so far, there appears to be greater overlap between T1D/CeD and T1D/RA than between CeD and RA. This may reflect the fact that larger sample sizes were used to investigate T1D (> 8,000 T1D cases vs >9,000 controls) than CeD (2,500 cases vs >9,000 controls), thereby reducing the possibility of false negative results in the T1D series. The lack of association of some of the CeD loci with RA could reflect lack of power, particularly if winner's curse has resulted in an overestimation of the effect sizes originally reported in the CeD studies. However, effect sizes observed when data from four GWAS of CeD were combined by meta-analysis were similar to those reported in the study by Smyth et al., which was used to select the CeD variants for testing in the current study [2, 13]. That suggests that winner's curse and over-estimation of effects sizes in CeD cannot explain the lack of association observed with RA.

The TAGAP minor allele confers protection against RA, similar to previous reports of T1D but contrasting with CeD in which the minor allele is associated with risk. Our results confirm and extend the evidence that there are common autoimmune susceptibility genes but suggest that the overlap of RA is stronger with TID than CeD.

Relatively little is known about the TAGAP gene, which encodes a protein (T-cell activation RhoGTPase activating protein) transiently expressed in activated T cells, suggesting that it may have a role in immune regulation [2].

The TAGAP gene has previously been associated with RA following meta-analysis of US and European RA cohorts, although a different variant mapping to the same locus was genotyped [11]. Nonetheless, the same UK samples tested as part of the current study were also included in the validation phase of the meta-analysis and so data for both variants was available. The results of conditional logistic regression analysis suggest that the primary effect is with the CeD variant tested in the current study and that the association reported previously with rs394581, may have arisen due to LD, at least in the UK samples.

It is interesting to note that the SNP tested at the CCR5 locus which is associated with both T1D and CeD, also showed a trend towards association with RA. A previous meta-analysis of studies in RA investigating this deletion variant within the gene is suggestive of association with RA [15]. A combined meta-analysis, including data from the previous meta-analysis, two subsequent reports [16] and the current data, reveals statistically significant evidence for association (P = 1.4 × 10^-5) but because of heterogeneity between the studies, these results should be interpreted with caution (Figure 1).

Exploring the genetic overlap between related diseases may reveal key common pathways that could suggest therapeutic targets applicable to more than one disease. However, the susceptibility loci unique to a particular disease are also of interest; differences may reflect genuine specificity between the diseases and may influence what determines the particular autoimmune phenotype. Of the confirmed non-HLA RA susceptibility loci (reviewed in [17]), only the CD40 and TRAF1/C5 variants have not been reported to be associated with either CeD or T1D although CD40 is associated with autoimmune thyroiditis [18]. Even the TRAF1/C5 association is not unique to RA as there have been reports of association with juvenile idiopathic arthritis and systemic lupus erythematosus [19, 20]. Despite the inherent bias arising from the fact that loci associated with one autoimmune disease are often subsequently targeted for investigation in other autoimmune diseases, the degree of genetic overlap is remarkable. One possible explanation may be that specificity of the autoimmune phenotype is determined by the particular HLA associations of each disease that could either directly or indirectly influence the response to environmental agents. This hypothesis would require further investigation in well-powered cohorts with both genetic and reliable environmental data.

In summary, we report association of RA with the TAGAP gene, identified through targeting loci previously associated with CeD. The findings identify that the same SNP associated with T1D and CeD shows stronger association with RA than a previously reported variant and extend the evidence for overlap between autoimmunity genes.

The TAGAP gene, previously associated with both T1D and CeD, is also associated with RA susceptibility. This confirms the finding of a previous study showing association of the TAGAP locus with RA but suggests that the variant associated with autoimmune diseases is more strongly associated than that reported previously.