Genetic Markers of Cardiovascular Disease in Rheumatoid Arthritis

Rodríguez‐Rodríguez, Luis; López‐Mejías, Raquel; García-Bermúdez, Mercedes; González‐Juanatey, Carlos; Martı́n, Javier

doi:10.1155/2012/574817

Cited by 37 publications

(36 citation statements)

References 135 publications

(147 reference statements)

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“…Since a growing body of evidence supports the notion of a genetic component in the risk of CVD in RA (for review, see ref. ), the potential association of rs662 variants with CVD in RA patients was further examined in some studies. Charles‐Schoeman and colleagues revealed that high PON‐1 activity (considered as either the R/R genotype or as serum PON‐1 activity) was protective against subclinical atherosclerosis development in RA.…”

Section: Discussionmentioning

confidence: 99%

Paraoxonase 1 Activity Is Modulated by the rs662 Polymorphism and IgG Anti–High‐Density Lipoprotein Antibodies in Patients With Rheumatoid Arthritis: Potential Implications for Cardiovascular Disease

Rodríguez‐Carrio

López‐Mejías

Alperi-López

et al. 2016

Arthritis & Rheumatology

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Objective Paraoxonase 1 (PON‐1) is a high‐density lipoprotein (HDL)–associated antioxidant enzyme that plays an important role in HDL‐mediated cardioprotection. Although genetic polymorphisms are known to modulate PON-1 activity, its involvement in cardiovascular disease (CVD) in rheumatoid arthritis (RA) is controversial, suggesting that other factors may modulate its function. Since anti‐HDL antibodies have been found to be related to an impaired lipid profile and occurrence of CVD in RA, this study was undertaken to examine the associations between PON-1 activity, anti‐HDL antibodies, and CVD according to PON1 genetic variants in patients with RA. Methods Serum PON-1 activity, using paraoxon as substrate, and IgG anti‐HDL antibodies were quantified in 212 RA patients and 110 healthy controls. The PON1 rs662 genotype (Q>R) was determined with TaqMan probes. An additional group of 13 biologics‐naive patients with RA was prospectively followed up for 3 months. Results PON‐1 activity was decreased in RA patients compared to healthy controls (P = 0.005), and an effect of the rs662 genotype was noted in both groups, with Q/Q homozygotes exhibiting the lowest PON‐1 activity. The distribution of rs662 genotypes did not differ between RA patients and healthy controls (P = 0.215). In patients carrying the Q/Q genotype, anti‐HDL antibodies were associated with impaired PON‐1 activity (P = 0.010), and levels of anti‐HDL antibodies were associated with decreased HDL levels (r = −0.680, P < 0.001) and higher prevalence of cardiovascular events, as determined in univariate and multivariate models. Furthermore, change in anti‐HDL antibody levels upon tumor necrosis factor blockade was an independent predictor of improved PON‐1 activity (β = −0.369, 95% confidence interval −0.669, −0.069; P = 0.024). Conclusion PON‐1 activity is impaired in RA in association with the rs662 genotype and anti‐HDL antibodies, the latter being recognized as a pivotal player in the link between rs662 and CVD in patients with RA.

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Section: Discussionmentioning

confidence: 99%

Paraoxonase 1 Activity Is Modulated by the rs662 Polymorphism and IgG Anti–High‐Density Lipoprotein Antibodies in Patients With Rheumatoid Arthritis: Potential Implications for Cardiovascular Disease

Rodríguez‐Carrio

López‐Mejías

Alperi-López

et al. 2016

Arthritis & Rheumatology

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“…Other studies exam ining the cardio vascular risk conferred by nonHLA alleles, such as TNF and other cytokineencoding genes, have had mixed results and, to date, the strongest genetic risk factors for cardiovascular mortality in RA are HLAassociated genes. 84 Disease phenotype RA is a heterogeneous disease with a range of outcomes for joint disease; the same variability is likely to apply to cardiovascular outcomes. A number of studies have found that risk of cardiovascular mortality is particularly increased in seropositive patients, 85,86 those with extra articular manifestations 87 (such as nodules) and those with higher levels of disability 86 (Box 2).…”

Section: Ra-related Factorsmentioning

confidence: 99%

Atherosclerosis in rheumatoid arthritis: is it all about inflammation?

2015

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Rheumatoid arthritis (RA) has long been associated with increased cardiovascular risk, but despite substantial improvements in disease management, mortality remains high. Atherosclerosis is more prevalent in RA than in the general population, and atherosclerotic lesions progress at a faster rate and might be more prone to rupture, causing clinical events. Cells and cytokines implicated in RA pathogenesis are also involved in the development and progression of atherosclerosis, which is generally recognized as an inflammatory condition. The two diseases also share genetic and environmental risk factors, which suggests that patients who develop RA might also be predisposed to developing cardiovascular disease. In RA, inflammation and atherosclerosis are closely linked. Inflammation mediates its effects on atherosclerosis both through modulation of traditional risk factors and by directly affecting the vessel wall. Treatments such as TNF inhibitors might have a beneficial effect on cardiovascular risk. However, whether this benefit is attributable to effective control of inflammation or whether targeting specific cytokines, implicated in atherosclerosis, provides additional risk reduction is unclear. Further knowledge of the predictors of cardiovascular risk, the effects of early control of inflammation and of drug-specific effects are likely to improve the recognition and management of cardiovascular risk in patients with RA.

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“…Genetic association studies have suggested a role for ACP1 in human cardiovascular disorders [12][13][14][15]. LMPTP appears to modulate signalling through several tyrosine kinase receptors [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress‐induced cardiomyopathy

Wade

Quijada

Al-Haffar

et al. 2015

The Journal of Pathology

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The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long‐term pressure overload. Acp1−/− mice develop normally and ageing mice do not show pathology in major tissues under basal conditions. However, Acp1−/− mice are strikingly resistant to pressure overload hypertrophy and heart failure. Lmptp expression is high in the embryonic mouse heart, decreased in the postnatal stage, and increased in the adult mouse failing heart. We also show that LMPTP expression increases in end‐stage heart failure in humans. Consistent with their protected phenotype, Acp1−/− mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of fibrotic genes. Transcriptional profiling and analysis of molecular signalling show that the resistance of Acp1−/− mice to pathological cardiac stress correlates with marginal re‐expression of fetal cardiac genes, increased insulin receptor beta phosphorylation, as well as PKA and ephrin receptor expression, and inactivation of the CaMKIIδ pathway. Our data show that ablation of Lmptp inhibits pathological cardiac remodelling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of human heart failure. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Genetic Markers of Cardiovascular Disease in Rheumatoid Arthritis

Cited by 37 publications

References 135 publications

Paraoxonase 1 Activity Is Modulated by the rs662 Polymorphism and IgG Anti–High‐Density Lipoprotein Antibodies in Patients With Rheumatoid Arthritis: Potential Implications for Cardiovascular Disease

Paraoxonase 1 Activity Is Modulated by the rs662 Polymorphism and IgG Anti–High‐Density Lipoprotein Antibodies in Patients With Rheumatoid Arthritis: Potential Implications for Cardiovascular Disease

Atherosclerosis in rheumatoid arthritis: is it all about inflammation?

Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress‐induced cardiomyopathy

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