Abstract
IntroductionRheumatoid 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.MethodsThree 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.ResultsMale 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).ConclusionsOur results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA.
Highlights
Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk
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% Confidence interval (CI) = 0.56 to 0.93, P = 0.012)
Our results reveal that Interferon regulatory factor 5 (IRF5) gene variants are associated with risk of CV events in patients with RA
Summary
Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Misregulated expression of type I IFN genes has been observed in peripheral white blood cells of patients with several autoimmune diseases [9]. In this regard, interferon regulatory factor 5 (IRF5) has been involved in the regulation of type I IFN gene transcription [10,11]. Interferon regulatory factor 5 (IRF5) has been involved in the regulation of type I IFN gene transcription [10,11] This protein is critical for the production of proinflammatory cytokines [12], such as TNF-α, interleukin 12 (IL-12) and IL-6, following Toll-like receptor signaling. IRF5 acts as a molecular switch that controls inflammatory mechanisms mediated by macrophage cells [12]
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