Background/Purpose

The use of biomarkers to predict response to the different drugs available for treating rheumatoid arthritis (RA) is a very desirable goal. However, success of the many studies already performed has been limited. Genetic studies of response to the TNF inhibitors (TNFi) have reported multiple associations. At least 14 are from relative large candidate gene studies including hundreds of patients and other 16 are from GWAS also with hundreds of patients. A couple of them, in the PTPRC and PDE3A-SLCO1C1 loci, have been replicated in a second study, but none has yet been confirmed with full confidence. We aimed to replicate here the 14 genetic associations proposed in large candidate gene studies.
Methods

We analyzed the response to TNFi treatment of 755 patients with RA naïve to biologic DMARDs and of European ancestry. They have been treated with the three most common TNFi (infliximab, N = 397; etanercept, N = 155; adalimumab, N = 203). Their response to these drugs was evaluated either as change in DAS28 (ΔDAS28) between baseline and 3, 6 and 12 months of treatment, or as classification according to the EULAR response criteria (good + moderate responders vs. non responders) at the same time points. The genotypes of the 14 previously associated SNPs plus the putative causal SNP at one of them were obtained with a single-base extension multiplex methodology. We considered the SNPs according to an additive genetic model in linear and logistic regression analyses, for ΔDAS28 and EULAR criteria, respectively. Baseline DAS28, gender and treatment were considered as covariates. Statistica 7.0 (Statsoft, Tulsa OK) software was used to perform these analyses.
Results

All the SNPs were successfully genotyped (call rate = 99.1 %; HWE P > 0.05). Only one of the 14 loci was associated with response to TNFi. This was the PTPRC SNP rs10919563 that is a confirmed RA susceptibility locus. The RA risk allele (G) of this SNP was associated with higher ΔDAS28 at 6 months (B = 0.33, [95% CI] 0.09 to 057, P = 0.006) and showed a trend to association with good response as defined with the EULAR criteria (odds ratio [OR] 1.49, [95% CI] 0.94 to 2.33, P=0.08). A second PTPRC SNP, rs6683595, very correlated with rs10919563, which is a putative causal polymorphism of this RA locus because it maps in an active regulatory region in CD4⁺ T_reg cells showed an even stronger association: its G allele was associated with higher ΔDAS28 at 6 months (B = 0.39, [95% CI] 0.18 to 0.61, P=0.0003) and with good response (OR = 1.56, [95% CI] 1.04 to 2.37, P= 0.03).
Conclusion

We have obtained a new replication of the association of the PTPRC RA risk locus with response to TNFi. In this way, it has become the most replicated to date of the genetic biomarkers of response to these drugs with three studies including hundreds of patients each showing consistent results. In addition, we have found stronger association with a putative causal polymorphism in this locus that pave the way for functional studies exploring its involvement in RA and its treatment.