Background/Purpose : Rheumatoid arthritis (RA) is a chronic inflammatory joint disease which is associated with an increased cardiovascular (CV) risk.. An important process in atherogenesis is cell growth and hyperplasia. Interferons (IFNs), especially IFNβ, are known inhibitors of vascular smooth muscle cell proliferation and intimal hyperplasia. Interferon regulatory factor 5 (IRF5) is a major regulator of IFN production and genetic variants in IRF5 are known to stimulate the consecutive production of type I IFNs. In the current study, we investigate the effect of IRF5 gene variants on preclinical atherosclerosis, measured with carotid intima media thickness (cIMT) in RA patients.

Methods : Peripheral blood DNA was obtained in a subgroup of 101 RA patients from the CARRÉ study. IRF5 SNPs rs2004640 was determined using Taqman Genotyping assay. cIMT was determined by B-mode ultrasonography. Linear regression analyses were used to investigate the association between cIMT and IRF5 genotypes, adjusted for demographic and cardiovascular factors (age, sex, cholesterol blood pressure and smoking). 

Results : RA patients carrying the rs2004640 T-allele have significant lower cIMT compared to homozygote G-allele carriers (P<0.005). This effect is stronger when patients are homozygous for the T allele compared to the wildtype allele (P<0.005). Age was shown to be an effect-modifier for the association and the strongest association between cIMT and rs2004640 was seen in patients older than 60. Linear regression analysis in patients older than 60 showed that the rs2004640 TT-genotype was associated with lower cIMT (regression coefficient -0.107 (C.I. -0.205; -0.008), p=0.035) which remained significant after adjustment for demographic and cardiovascular risk factors (regression coefficient -0.111 (C.I.-0.202; -0.02), p=0.020). 

Conclusion :

We demonstrate for the first time that the IRF5 gene variant rs2004640, which is associated with enhanced type I IFN activity, is associated with preclinical atherosclerosis in RA patients, independent of cardiovascular risk factors. The genetic variant of IRF5 rs2004640 T-allele, which leads to enhanced type I IFN levels, is related to lower cIMT in RA. As reduced activity of IFN-beta is highly associated with both atherosclerosis and inflammation, these results might implicate IFN as an important cytokine responsible for the increased rate of CV disease in RA.