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
and now TAGAP
are susceptibility loci that are common to the three autoimmune diseases examined in the current study: T1D, CeD and RA [2
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
]. 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
]. 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
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 ).
Meta-analysis of studies investigating a deletion in the CCR5 gene with RA susceptibility.
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
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
]. 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.