Background Rheumatoid Arthritis is a chronic inflammatory condition associated with increased cardiovascular disease (CVD) morbidity and mortality due to high coronary and cerebral atherosclerotic burden. Assymetric dimethylarginine (ADMA) – the most potent endogenous inhibitor of nitric oxide synthase - is an emerging marker of endothelial dysfunction and CVD in several conditions such as coronary artery disease and diabetes mellitus. ADMA levels are higher in RA patients compared to controls suggesting a role in the development of atherosclerosis. In addition ADMA is involved in the metabolism of honocysteine (Hcy) which is considered a novel, non-traditional CVD risk factor contributing to excess CVD risk in this population.

Objectives The aim of our study was to determine whether asymmetric dimethylarginine (ADMA) levels are associated with Hcy and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) gene variants in patients with RA.

Methods Serum ADMA and Hcy levels were measured in 201 RA individuals [155 (77.1%) females, median age 67 years (interquartile range 59–73)]. The MTHFR C677T polymorphism was assessed by using the LightCyclerTM System. Initially, ADMA was compared across the categories of MTHFR using a one-way analysis of variance (ANOVA), followed by a multivariate model, which accounted for Hcy, age, erythrocyte sedimentation rate (ESR), and homeostatic model assessment (HOMA).

Results In univariable analysis, ADMA differed significantly across the categories of MTHFR (p=0.037). Patients with the MTHFR 677TT genotype had the highest ADMA levels, with a mean of 0.62 (SE =0.03), significantly higher than either those patients carrying the MTHFR 677CT (0.55, SE =0.01) or the MTHFR 677CC (0.55, SE=0.01) genotype (p=0.042) in both cases. In the multivariable model, Hcy (p=0.022) and ESR (p<0.001) were found to have significant positive associations with ADMA but the relationship between MTHFR gene variants and ADMA was found to be non-significant (p=0.102).

Conclusions The results of our study indicate an association between ADMA and Hcy in patients with RA without any genetic background as no relationship was established between ADMA and MTHFR gene variants. Abnormal metabolism of Hcy and dimethylarginines may interfere with each other resulting in endothelial dysfunction and accelerated atherosclerosis in RA individuals.

References

1. Dimitroulas T, Sandoo A, Hodson J, Smith J, Douglas K, Kitas G. MTHFR C677T Polymorphism but not DDAH gene variants are associated with Assymetric Dimethylarginine (ADMA) in RA. Ann Rhem Dis 2014;72(Suppl 2):333.

2. Perna M, Roman MJ, Alpert DR, Crow MK, Lockshin MD, Sammaritano L, et al. Relationship of asymmetric dimethylarginine and homocysteine to vascular aging in systemic lupus erythematosus patients. Arthritis Rheum 2010;62:1718–22.

References

Disclosure of Interest None declared