Background Endothelial dysfunction is highly prevalent in patients with Rheumatoid Arthritis (RA) contributing to the excess cardiovascular (CV) risk observed in this population. Assymetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and it represents a newly discovered marker of atherosclerosis. ADMA is intracellularly hydrolyzed into citrulline and dimethylamine by the dimethylarginine dimethylaminohydrolase (DDAH). Systemic inflammation reduces DDAH activity and this has been suggested as a potent mechanism for high ADMA levels in RA. Methylenetetrahydrofolate reductase (MTHFR) is involved in the metabolic pathway of methionine and has been linked with increased CV risk in RA.
Objectives To determine whether DDAH 1 and 2 gene polymorphisms and MTHFR C677T polymorphism are associated with high ADMA levels in RA.
Methods Serum ADMA levels were measured in 201 individuals with RA [155 females median age 67 (59 – 73)]. Four tag SNPs in DDAH1 gene and 2 in the DDAH2 gene were genotyped. MTHFR C677T polymorphism was assessed by using the LightCyclerTM System. ADMA was initially compared across the genetic variables using one-way ANOVA and then multivariate analysis examined each of the genes after adjustment for parameters of systemic inflammation and insulin resistance, namely erythrocyte sedimentation rate (ESR) and homeostatic model assessment (HOMA), which we have previously shown affect ADMA levels in RA.
Results Patients with polymorphism in the MTHFR C677T gene had significantly increased ADMA levels relative to normal or carriers of the gene (0.62 and 0.55 respectively, p=0.042). In multivariate analysis (which included ESR and HOMA), MTHFR C677T polymorphism independently associated with ADMA (p =0.04). In contrast no relationship between DDAH gene variants and ADMA was established.
Conclusions These findings suggest that MTHFR C677T gene polymorphism plays an important role in premature atherosclerosis in RA by promoting ADMA accumulation and leading to the derangement of vascular haemostasis. The significance of DDAH/ADMA pathway in endothelial dysfunction in these patients remains unclear and warrants further investigation.
Dimitroulas T, Sandoo A, Kitas GD: Asymmetric dimethylarginine as a surrogate marker of endothelial dysfunction and cardiovascular risk in patients with systemic rheumatic diseases. Int J Mol Sci 2012; 13:12315-12335.
Fogarty RD, Abhary S, Javadiyan S, Kasmeridis N, Petrovsky N, Whiting MJ, Craig JE, Burdon KP. Relationship between DDAH gene variants and serum ADMA levelin individuals with type 1 diabetes. J Diabetes Complications. 2012;26:195-8.
Palomino-Morales R, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Rodriguez L, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J, Martin J, Gonzalez-Gay MA. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res Ther. 2010;12(2):R71.
Disclosure of Interest : None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.