THU0113 Genetic Variations in The Alanine-Glyoxylate Aminotransferase-2 (AGXT-2) Gene Are Not Related To Levels of Dimethylarginines in Patients with Rheumatoid Arthritis. (15th July 2016) - Dimitroulas, T.
Abstract : Background: Rheumatoid arthritis (RA) is associated with high rates of cardiovascular (CV) events and increased CV morbidity and mortality mainly due to coronary and cerebrovascular atherosclerotic disease. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines are endogenous inhibitors of nitric oxide synthase and have been repeatedly linked with adverse CV outcomes in the general population and various disease settings. ADMA and SDMA levels differ in RA individuals compared to non-RA subjects but whether such abnormalities are driven by genetic variations remains under investigation. Objectives: The aim of the current study was to investigate the effect of alanine-glyoxylate aminotransferase-2 (AGXT-2) gene polymorphisms on circulating levels of ADMA and SDMA in RA patients. Methods: Serum ADMA and SDMA levels were measured in 201 individuals with RA [155 females median age 67 (59–73)]. Two tag SNPs in AGXT-2 gene – rs37369 and rs28305 – were genotyped. Distributions of SDMA and ADMA were skewed, hence comparisons across the gene polymorphisms were performed using Mann-Whitney tests, and summarised using medians and interquartile ranges. Multivariate analysis examined each of the genes after adjustment for parameters of systemic inflammation, insulin resistance and renal function namely [erythrocyte sedimentation rate (ESR), quantitative insulin sensitivity check index (QUICKI) and estimated glomerular filtration rate (EGFR)] which we have previously shown affect ADMA and SDMA levels in RA. Results: Univariable analysis found no evidence to suggest that either SDMA or ADMA differed significantly between the categories of rs37369AGXT2 (p=0.911, 0.507) or rs28305AGXT2 (p=0.233, 0.501). A multivariable analysis was then performed, which accounted for potential confounding factors. This showed ESR (p<0.001) and EGFR (p=0.007) to be significantly associated with ADMA, whilst QUICKI (p=0.029) and EGFR (p<0.001) were significantly associated with SDMA. Conclusions: Our study in a well-characterized RA population did not show any associations between serum concentrations of dimethylarginines and gene variants of AGXT2, as reported to occur in the general population and patients with diabetic mellitus. References: Dimitroulas T, Hodson J, Sandoo A, Smith J, Kitas GD. Symmetric dimethylarginine (SDMA) serum levels in rheumatoid arthritis: correlations with insulin resistance and disease activity scores. Amino Acids.2015;47:1995–2004. Sandoo A, Dimitroulas T, Hodson J, Smith JP, Douglas KM, Kitas GD. Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study. Rheumatology (Oxford). 2015;54:1145–52. Lüneburg N, Lieb W, Zeller T, Chen MH, Maas R, Carter AM, et al. Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. Circ Cardiovasc Genet. 2014;7:864–72. Disclosure of Interest: None declared