Rheumatoid arthritis (RA) is a complex polygenic autoimmune inflammatory disease characterized by persistent synovitis and joint damage. Several genetic polymorphisms, such as HLA-DRB1, PTPN22, STAT4, TRAF1/C5 and TNFAIP3, have been implicated in the susceptibility to RA 1 . On the other hand, increased cardiovascular (CV) mortality is observed in patients with RA. This is the result of accelerated atherogenesis 2 3 4 .

Acid phosphatase locus 1 (ACP1) is a gene located on chromosome 2p25 that encodes a low molecular weight phosphotyrosine phosphatase (LMW-PTP), which presents two main enzymatic activities: phosphoprotein tyrosine phosphatase and flavin mononucleotide phosphatase 5 . Two different isoenzymes of LMW-PTP have been described: 'fast' (also noted as ACP1-F(fast), isoform 1, IF1, HCPTP-A) and 'slow' (also noted as ACP1-S(slow), isoform 2, IF2, HCPTP-B), that arise through alternative splicing mechanisms, in which either exon 3 or exon 4 is excised and the other retained respectively 5 6 . These two LMW-PTP isoenzymes have different molecular and catalytic properties, suggesting that they may be implicated in different biological functions in the cell 5 7 . In Caucasian populations there are three common codominant alleles of ACP1, ACP1*A, ACP1*B, ACP1*C. ACP1 alleles differ on single-nucleotide polymorphisms (SNPs), which affect both the total enzymatic activity and the ratio between isoforms F/S, being the ratio F/S 2:1 in ACP1*A, 4:1 in ACP1*B and 1:4 in ACP1*C 5 7 8 .

LMW-PTP is considered to play a key role as regulator of signaling pathways in receptor-stimulated immune cells 9 . LMW-PTP has also been involved in the regulation of many growth factors such as platelet-derived growth factor receptor (PDGFR) 10 , fibroblast growth factor receptor (FGFR) 11 , insulin receptor (IR) 12 13 and EphA2 receptor, a ligand that binds to the Ephrin family of signaling molecules 14 . LMW-PTP has also been implicated in the regulation of ZAP70 Kinase (ζ-chain- associated protein kinase of 70 kDa) 15 playing a role in T-cell development and lymphocyte activation, enhancing signaling from the T cell antigen receptor 15 . Additionally, LMW-PTP has been found to be a key mediator in the integrin signaling during cellular adhesion 9 .

Allelic polymorphisms of the ACP1 gene have been associated with susceptibility to several human diseases, including inflammatory and autoimmune diseases 5 16 . Interestingly, the ACP1 gene was also associated with susceptibility to coronary atherosclerotic artery disease (CAD) 17 .

Taking into account the possible influence that ACP1 may have in the susceptibility to immune-mediated disorders and in the pathogenesis of the CV disease, in the present study we aimed to investigate the possible association of ACP1 alleles with the susceptibility to RA as well as whether ACP1 gene polymorphism may contribute to the increased risk of CV complications observed in patients with RA.

Since the association of ACP1 gene with autoimmunity has previously been described 5 , in the present study we sought to investigate the possible association of ACP1 polymorphisms with RA. Furthermore, taking into account that this gene has been involved in the susceptibility to CAD 17 , we also assessed whether ACP1 variations could be involved in the risk of CV events in patients with RA. Our result revealed that ACP1 polymorphisms do not influence the susceptibility to RA. However, these polymorphisms seem to influence the risk of CV events in these patients. In this regard, both rs11553742*T and ACP1*C alleles increased the risk of CV complications in patients with RA. Interestingly, rs11553742*T has been observed to decrease the F/S ratio of the LMW-PTP isoenzymes 5 ; in this regard the ACP1*C allele, carrier of the minor allele of rs11553742, was found to produce a major amount of S isoforms and is also associated with the highest total LMW-PTP activity 8 23 .

Our results are in accordance with the findings by Banci et al. 17 , who observed that high S isoform genotypes were associated with increased risk to develop CAD. Moreover, patients with hypertrophic cardiomyopathy, an autosomal dominant disease, were found to have the highest frequencies for ACP1*C allele and showed a linear relationship between maximum wall thickness and the amount of total LMW-PTP activity 16 .

The effect of the ACP1*C allele in the development of CV events could be explained by its possible role in the regulation of the energy metabolism and oxidative stress through its flavin mononucleotide phosphatase activity 8 . With respect to this, a negative interaction between LMW-PTP and the enzyme glutathione reducatase (GSR), which affects the cellular concentration of their cofactor flavin adenosine dinucleotide (FAD), has been described 8 . GSR is a flavoenzyme involved in the cellular antioxidant mechanism that reduces oxidized glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH) that is an important cellular antioxidant. Low LMW-PTP activity increases the levels of cofactor flavin adenine dinucleotide (FAD) in the cytosol leading to increased activity of GSR; while higher LMW-PTP activity yields low GSR activity. Accordingly, low activity of GSR has also been found to be significantly associated with hypertension 24 , and it has also been considered to be a risk factor for CV by influencing cholesterol levels 25 . Furthermore, Bottini et al. 26 reported that the ACP1*A allele, the opposite allelic combination of ACP*C, is a protective factor for hypertriglyceridemia and hypercholesterolemia in obese women.

RA is a complex polygenic disease and, besides the association of HLA-DRB1*04 shared epitope alleles with CV disease 4 27 , recent reports have also emphasized the potential implication of other gene polymorphisms in the increased risk of CV events observed in patients with RA. In this regard, interactions between NOS gene polymorphisms and HLA-DRB1*04 shared epitope alleles seem to confer an increased risk of developing CV events in these patients 28 . Also, the A1298C polymorphism in the MTHFR gene was found to predispose to CV risk in RA 29 . More recently, an association of the TNFA rs1800629 gene polymorphism with predisposition to CV complications in RA patients carrying the rheumatoid shared epitope was also described 30 .

Our data show for first time the association of the ACP1*C allele with increased susceptibility to CV events in patients with RA. This effect may be based on the major production of the S isoform of LMW-PTP by this allele, which may influence the regulation of energy metabolism and the response to oxidative stress.

ACP1: acid phosphatase locus 1; ACPA: anti-cyclic citrullinated peptide antibodies; ACR: American College of Rheumatology; CAD: coronary atherosclerotic artery disease; CI: confidence intervals; CV: cardiovascular; FAD: flavin adenosine dinucleotide; FGFR: fibroblast growth factor receptor; GSH: glutathione; GSR: glutathione reducatase; GSSR: glutathione disulfide; HWE: Hardy-Weinberg equilibrium; IR: insulin receptor; LMW-PTP: low molecular weight phosphotyrosine phosphatase; MAF: minor allele frequency; OR: Odds ratio; PCR: polymerase chain reaction; PDGFR: platelet-derived growth factor receptor; RA: rheumatoid arthritis; SNP: single-nucleotide polymorphism.

The authors declare that they have no competing interests.

MT, JEM, NB and JM made substantial contributions to the conception and design of the study, and the interpretation of data. MT carried out genotyping, analysis of data and drafted the manuscript. JEM carried out genotyping. CGJ, RLM, JAMF, RB, AB, DPS, LRR, BFG, AMO, IGA and CGV were involved in the acquisition of cardiovascular data in the different Spanish hospitals included in this study. JL carried out the analysis and interpretation of the data. JM and MAGG were involved in revising the manuscript and gave final approval of the version to be published.