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Open Access Highly Accessed Research article

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

Mercedes García-Bermúdez1, Raquel López-Mejías2, Fernanda Genre2, Santos Castañeda3, Javier Llorca4, Carlos González-Juanatey5, Alfonso Corrales2, Begoña Ubilla2, José A Miranda-Filloy6, Trinitario Pina2, Carmen Gómez-Vaquero7, Luis Rodríguez-Rodríguez8, Benjamín Fernández-Gutiérrez8, Alejandro Balsa9, Dora Pascual-Salcedo9, Francisco J López-Longo10, Patricia Carreira11, Ricardo Blanco2, Javier Martín1 and Miguel A González-Gay122*

Author Affiliations

1 Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n, Armilla, 18100 Granada, Spain

2 Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Avenida Cardenal Herrera Oria s/n, 39011 Santander, Spain

3 Department of Rheumatology, Hospital Universitario la Princesa, IIS-Princesa, Diego de León 62, 28006 Madrid, Spain

4 Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IDIVAL, Avenida Cardenal Herrera Oria s/n, 39011 Santander, Spain

5 Cardiology Division, Hospital Universitario Lucus Augusti, Doctor Ochoa s/n, 27004 Lugo, Spain

6 Department of Rheumatology, Hospital Universitario Lucus Augusti, Doctor Ochoa s/n, 27004 Lugo, Spain

7 Department of Rheumatology, Hospital Universitario Bellvitge, Feixa Llarga s/n, 08907 Barcelona, Spain

8 Department of Rheumatology, Hospital Clínico San Carlos, Profesor Martín Lagos s/n, 28040 Madrid, Spain

9 Department of Rheumatology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain

10 Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain

11 Department of Rheumatology, Hospital Universitario 12 de Octubre, Avenida de Córdoba s/n, 28041 Madrid, Spain

12 Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 1 Jan Smuts Avenue Braamfontei, 2000 Johannesburg, South Africa

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Arthritis Research & Therapy 2014, 16:R146  doi:10.1186/ar4608

Published: 10 July 2014

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.