Interferon regulatory factor 5 genetic variants are associated with cardiovascular disease in patients with rheumatoid arthritis

Open Access

Abstract

[Introduction] Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction. Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders. In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients. ; [Methods] Three IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA. Among them, 390 (18.2%) had experienced CV events. The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression. ; [Results] Male sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population. Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively). Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012). ; [Conclusions] Our results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA. ; This study was supported by European Union FEDER funds (European Fund for Regional Development) and the Health Research Fund (Fondo de Investigación Sanitaria grants PI06/0024, PS09/00748 and PI12/00060) from Instituto de Salud Carlos III (ISCIII, Health Ministry, Spain). It was also partially supported by Cooperative Health Research Thematic Network (RETICS) Program RD12/0009 (RIER) from Instituto de Salud Carlos III (ISCIII, Health Ministry, Spain) and by grants from the European Innovative Medicines Initiative Be the Cure (IMI BTCure) program. RLM is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto Carlos III de Salud at the Spanish Ministry of Health (CD12/00425). FG and BU are supported by funds from the RETICS Program (RIER) (RD12/0009/0013). ; Peer reviewed