Interaction Between Antibodies to Paraoxonase 1 and PON1 rs662 Polymorphism: New Clues to Understand HDL Dysfunction and Oxidative Stress in Rheumatoid Arthritis

Javier Rodríguez-Carrio¹, Mercedes Alperi-López², Raquel López-Mejías³, Patricia López¹, Francisco Javier Ballina-García², Francisco Abal⁴, Miguel Angel Gonzalez-Gay^3,5 and Ana Suárez¹, ¹Area of Immunology, Department of Functional Biology, University of Oviedo, Oviedo, Spain, ²Department of Rheumatology, Hospital Universitario Central de Asturias, Asturias, Spain, ³Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL, Santander, Spain, ⁴Centro de Salud Sariego, Siero, Servicio de Salud del Principado de Asturias (SESPA), Siero, Spain, ⁵School of Medicine, University of Cantabria, Santander, Spain

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: autoantibodies, Cardiovascular disease, paraoxonase and rheumatoid arthritis (RA)

Session Information

Date: Monday, November 14, 2016

Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Traditional and non-traditional cardiovascular (CV) risk factors underlie CV disease occurrence in rheumatoid arthritis (RA). Recently, a functional impairment of HDL antioxidant capacity has been observed. Although the actual players are unknown, anti-HDL antibodies have been associated with altered lipid profile, decreased paraoxonase 1 (PON1) activity and CV disease in RA patients. Therefore, we aimed to evaluate whether the presence of antibodies against PON1 may be involved in this scenario.

Methods: IgG anti-PON1 antibodies were quantified by ELISA in serum samples from 175 healthy controls (HC), 54 subjects with traditional CV risk factors and 212 RA patients (all fulfilling 2010 ACR/EULAR classification criteria, 56.1% RF+, 57.0% ACPA+, DAS28 median (IQR) 3.73 (2.24)). A subgroup of 13 RA patients was prospectively followed upon TNFa-blockade for 3 months. PON1 activity and total antioxidant capacity (TAC) were measured in serum. IFNg, IL-8, MCP-1, VEGF, sICAM and TNFa serum levels were assessed by immunoassays. PON1 rs662 (Q>R) status was studied by RT-PCR.

Results: IgG anti-PON1 antibodies are increased in RA patients compared to HC (p<0.0001) and CVR groups (p<0.001), even after correcting for total IgG levels. Although no associations with lipid profile were found, a positive correlation with HAQ was observed (r= 0.215, p=0.004). An ANCOVA analysis confirmed an independent effect of both rs662 status (p<0.0001) and anti-PON1 levels (p=0.015) on PON1 activity, these associations remain after adjusting for disease parameters. Anti-PON1 antibodies were negatively associated with PON1 activity and TAC, a rs662-mediated gene-dosage effect being found. The association between anti-PON1 and TAC mirrored that of found between PON1 and TAC (Table 1) after stratifying by rs662 variants. Similarly, anti-PON1 antibodies were correlated to sICAM serum levels in univariate (r= 0.226, p=0.010) and multivariate models (B[95% CI], p: 0.159 [0.065, 0.2253], <0.001). Finally, anti-PON1 serum level and TAC were not affected by TNFa-blockade.

Conclusion: Anti-PON1 antibodies can be responsible of 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. Overall, anti-PON1 may be the missing link between autoimmunity, oxidative stress and CV disease in RA.

Table 1
	QQ (n=95)	QR (n=69)	RR (n=22)	p-value
Anti-PON1/IgG	11.12 (35.62)	12.60 (35.33)	14.19 (68.39)	0.548
PON1 activity (U)	217.57±86.08	345.96±115.12	418.33±101.17	<0.0001
TAC (mM, T-Eq)	3.99±0.91	3.71±0.86	3.85±0.91	0.106
sICAM-1 (pg/ml)	226.80 (168.92)	273.25 (208.56)	244.31 (278.16)	0.507
Correlations (r, p)
Anti-PON1 – PON1 activity	r= -0.369 p=0.0002	r= -0.158 p=0.199	r= -0.310 p=0.160
Anti-PON1 – TAC	r= -0.290 p=0.015	r= -0.259 p=0.056	r= 0.150 p=0.567
PON1 activity – TAC	r= 0.325 p=0.006	r=0.154 p=0.241	r=0.123 p=0.639

Disclosure: J. Rodríguez-Carrio, None; M. Alperi-López, None; R. López-Mejías, None; P. López, None; F. J. Ballina-García, None; F. Abal, None; M. A. Gonzalez-Gay, None; A. Suárez, None.

To cite this abstract in AMA style:

Rodríguez-Carrio J, Alperi-López M, López-Mejías R, López P, Ballina-García FJ, Abal F, Gonzalez-Gay MA, Suárez A. Interaction Between Antibodies to Paraoxonase 1 and PON1 rs662 Polymorphism: New Clues to Understand HDL Dysfunction and Oxidative Stress in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/interaction-between-antibodies-to-paraoxonase-1-and-pon1-rs662-polymorphism-new-clues-to-understand-hdl-dysfunction-and-oxidative-stress-in-rheumatoid-arthritis/. Accessed .

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/interaction-between-antibodies-to-paraoxonase-1-and-pon1-rs662-polymorphism-new-clues-to-understand-hdl-dysfunction-and-oxidative-stress-in-rheumatoid-arthritis/