Although several clinical and serologic risk factors for RA severity are known, thus far, the interindividual variance in joint destruction is insufficiently explained and genetic factors are scarcely investigated. A better comprehension of the factors that mediate joint damage in RA may lead to the development of targeted therapies or may contribute to the prediction of disease outcome in individual RA patients. Most recently, 6 new loci were reported to predispose to autoantibody-positive RA (2
). Although susceptibility factors do not necessarily affect disease progression, we investigated whether these 6 SNPs were also risk factors for a severe course of RA, as measured by the rate of joint damage. The present data suggest that 2 SNPs, rs4810485 (CD40
) and rs42041 (CDK6
), influence the rate of joint destruction in ACPA-positive RA. Of these, only rs4810485 was significantly associated after correction for multiple testing, and the association was replicated in an independent cohort of ACPA-positive RA patients. Thus, CD40
is the first non–HLA-related genetic risk factor for RA severity that has been independently replicated.
A recent study (2
) identified a common variant at the CD40
locus (the minor T allele) as being protective against the development of RA. Surprisingly, in our study, the minor T allele associated with a higher rate of joint destruction in 2 cohorts. This finding is counterintuitive if one assumes that genetic variants associating with susceptibility also associate with severity. Although our findings were observed in 2 independent cohorts, and were thus replicated, a type I error cannot be ruled out. The disease-associated (common) allele marks a haplotype of CD40
that contains a polymorphism in the upstream Kozak sequence that results in increased surface expression on B cells (8
). To our knowledge, the effect of this haplotype on CD40 surface expression in synovial fibroblasts has not been directly studied. However, CD40 expression is increased on synoviocytes in RA, and triggering of CD40 in synovial fibroblasts is associated with the production of proinflammatory cytokines and osteoclastogenesis (9
). It is likely that the biologic pathways underlying susceptibility and severity are distinct with respect to the triggering of CD40. This would provide an explanation for the finding that the minor T allele has a protective effect in susceptibility studies but is associated with a more severe disease course. Clearly, it is essential to perform further studies on the mechanisms by which CD40
polymorphisms associate with erosive outcome in RA.
A second SNP, rs42041, tended to associate with the rate of joint damage in RA in the EAC cohort. Lack of replication in the NARAC cohort indicates that the observed association with the progression rate in the EAC cohort cannot be interpreted. Nonetheless, it will be interesting to see the results of other studies analyzing CDK6 and RA severity. Thus, at present, of the 2 SNPs that tended to show an association with the rate of joint destruction, only the genetic variant in CD40 was statistically significant after correction for multiple testing and was replicated in a second cohort; this variant in CD40 is therefore identified as a severity factor for RA.
The other 4 SNPs we examined in the loci encoding for KIF5A
, and MMEL1
were not observed to associate with the severity of joint destruction. Therefore, these polymorphisms appear to be genetic risk factors that are primarily associated with RA susceptibility. Indeed, all of these SNPs were recently replicated as being true susceptible loci in RA patients of European ancestry (11
The prospective nature of the data from the EAC cohort strengthens the impact of the findings because higher radiologic scores for risk genotypes were present at subsequent time points; as such, the present data set is advantageous in comparison to studies that assessed cross-sectional radiologic data. The fact that a large number of patients with a followup of as long as 9 years were included for analysis is clearly an advantage, but also has a limitation. Inherent in the design of an inception cohort is the fact that not all patients had achieved maximum followup, so the number of missing data that the mixed model had to take into account increased with longer followup. Small numbers of radiographs available at the latest time points are also the most likely explanation for the observed “bump” at the 8-year time point for genotypes GG, CC, and TT of SNPs rs2812378, rs4750316, and rs6684865, respectively ().
Evaluation of the effect of genetic factors on the rate of joint destruction during the disease course inevitably implies that other factors that affect the disease course should be taken into consideration as well. Analyses of all 6 SNPs revealed that the inclusion period, a proxy for treatment strategy, was significantly associated with the rate of joint damage, which is consistent with previous results from the EAC cohort (12
). The analyses of CD40
showed that these SNPs were associated with joint damage, independently of the treatment strategy. Nevertheless, corrections for treatment strategy were made at the group level and, thus, were an approximation of the real effect of treatment on the rate of joint destruction in individual RA patients.
In conclusion, a polymorphism in the CD40 locus showed a significant association with the rate of joint destruction in ACPA-positive RA patients, a finding that was replicated in an independent cohort. Although further studies are needed to identify the causal variant, the data presented provide a foundation for further investigations of the role of CD40 in joint destruction of RA.