Abstract
IntroductionWe 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.MethodsSix 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.ResultsNo 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).ConclusionsOur results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.
Highlights
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)
In a further step we aimed to determine whether these two functional MTHFR gene polymorphisms might be associated with the increased incidence of CV events observed in patients with RA. We assessed whether these two MTHFR gene polymorphisms might be associated with an increased risk of and subclinical atherosclerosis manifested by the presence of endothelial dysfunction in RA
No significant differences in the age at onset of the disease, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, shared epitope, and age at the time of disease diagnosis were observed according to the different MTHFR genotypes in the series of RA patients
Summary
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 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. Besides classic CV risk factors, a number of nontraditional CV risk factors have been implicated in the elevated CV mortality observed in these patients [2]. In this regard, chronic inflammation and the genetic background increase the risk of CV events in RA regardless of the presence of traditional CV risk factors [3]. Some investigators have advocated supplementation with folic acid for long-term, low-dose MTX therapy, since folic acid supplementation prevents MTX toxicity and hyperhomocysteinemia [9]
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