Open Access Open Badges Research article

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis

Rogelio Palomino-Morales1, Carlos Gonzalez-Juanatey2, Tomas R Vazquez-Rodriguez3, Luis Rodriguez4, Jose A Miranda-Filloy3, Benjamin Fernandez-Gutierrez4, Javier Llorca5, Javier Martin1 and Miguel A Gonzalez-Gay36*

Author Affiliations

1 Instituto de Parasitología y Biomedicina Lopez-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n Armilla, Granada 18100, Spain

2 Cardiology Division, Hospital Xeral-Calde, c/Dr. Ochoa, Lugo 27004, Spain

3 Rheumatology Division, Hospital Xeral-Calde, c/Dr. Ochoa, Lugo 27004, Spain

4 Rheumatology Service, Hospital Clínico San Carlos, c/Profesor Martín Lagos, S/N Madrid 28040, Spain

5 Division of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), Avda. Herrera Oria s/n, 39011 Santander, Spain

6 Rheumatology Division, Hospital Universitario Marques de Valdecilla, Avenida de Valdecilla s/n, 39008, Santander, Spain

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Arthritis Research & Therapy 2010, 12:R71  doi:10.1186/ar2989

Published: 26 April 2010



We determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA.


Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays.


No significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005).


Our results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.