title: Antibodies to paraoxonase 1 are associated with oxidant status and endothelial activation in rheumatoid arthritis.
abstract: Traditional and non-traditional cardiovascular (CV) risk factors underlie CV disease occurrence in rheumatoid arthritis (RA). Recently, a functional impairment of high-density lipoprotein (HDL) has been observed. Although the actual players are unknown, anti-HDLs were associated with altered lipid profile, decreased paraoxonase 1 (PON1) activity and CV disease in RA. Therefore, we aimed to evaluate whether the presence of antibodies against PON1 may be involved in this scenario. IgG anti-PON1 antibodies were quantified by ELISA in serum samples from 212 RA patients, 175 healthy controls (HC) and 54 subjects with traditional CV risk factors (CVR). A subgroup of 13 RA patients was prospectively followed upon tumour necrosis factor-α  (TNFα) blockade. Serum PON1 activity, nitric oxide (NO) and total antioxidant capacity (TAC) were measured. Interferon-γ (IFNγ), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule (sICAM) and TNFα serum levels were assessed by immunoassays. PON1 rs662 (Q > R) status was studied by reverse transcription (RT)-PCR. IgG anti-PON1 antibodies are increased in RA patients compared with HC (P<0.0001) and CVR subjects (P<0.001), even after correcting for total IgG levels. Although no associations with lipid profile were found, a positive correlation with Health Assessment Questionnaire (HAQ) was observed (r=0.215, P=0.004). Anti-PON1 antibodies were associated with PON1 activity, NO and TAC, a rs662-mediated gene-dosage effect being found. Similarly, anti-PON1 antibodies were associated with sICAM serum levels in univariate and multivariate models. Finally, these antibodies were not affected by TNFα blockade. Anti-PON1 antibodies can be responsible for PON1 impairment in RA patients, with a potential impact on biomarkers of oxidative status and endothelial activation. A gene-environment interaction of rs662 variants is supported.
authors: Area of Immunology, Department of Functional Biology, University of Oviedo, 33006 Asturias, Spain Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), 33300 Asturias, Spain.
authors: Javier
authors: J
authors: Rodríguez-Carrio
authors: Department of Rheumatology, Hospital Universitario Central de Asturias, 33011 Asturias, Spain.
authors: Mercedes
authors: M
authors: Alperi-López
authors: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, Hospital Universitario Marqués de Valdecilla, IDIVAL, 39011 Santander, Spain.
authors: Raquel
authors: R
authors: López-Mejías
authors: Area of Immunology, Department of Functional Biology, University of Oviedo, 33006 Asturias, Spain.
authors: Patricia
authors: P
authors: López
authors: Department of Rheumatology, Hospital Universitario Central de Asturias, 33011 Asturias, Spain.
authors: Francisco J
authors: FJ
authors: Ballina-García
authors: Centro de Salud Sariego, Servicio de Salud del Principado de Asturias, 33518 Asturias, Spain.
authors: Francisco
authors: F
authors: Abal
authors: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, Hospital Universitario Marqués de Valdecilla, IDIVAL, 39011 Santander, Spain Department of Medicine, University of Cantabria, 39011 Santander, Spain Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 2193 Johannesburg, South Africa.
authors: Miguel Á
authors: MÁ
authors: González-Gay
authors: Area of Immunology, Department of Functional Biology, University of Oviedo, 33006 Asturias, Spain anasua@uniovi.es.
authors: Ana
authors: A
authors: Suárez
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000276:immunology; D043303:Aryldialkylphosphatase / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000906:Antibodies; D015415:Biomarkers; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma; D043303:Aryldialkylphosphatase
keywords: anti-paraoxonase 1 antibodies; cardiovascular disease; high-density lipoproteins; paraoxonase; rheumatoid arthritis