Background/Purpose: RA is associated with the development of cardiovascular (CV) disease and subclinical atherosclerosis, which leads to an increased risk of CV mortality in RA patients¹. The presence of carotid plaques assessed by ultrasonography studies is a surrogate marker for subclinical atherosclerosis². Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in homeostasis of cholesterol, a traditional CV risk factor related to RA and atherosclerosis^1,3. PCSK9 polymorphisms can both increase and decrease the risk of CV disease in patients with atherosclerosis³. However, there are no information on PCSK9 polymorphisms in RA. In the present study, we assess the role of several PCSK9 polymorphisms in RA as well as determine if these ones may influence on PCSK9 protein levels.

Methods: PCSK9 rs562556, rs505151, rs2495477, rs2483205, rs2495482, rs2479409, rs11591147 and rs11583680 polymorphisms were genotyped in 1,170 Spanish RA patients, who met the 1987 ACR and the 2010 ACR/EULAR criteria for RA^4-5, and 528 healthy controls. Hardy-Weinberg equilibrium and allelic frequencies for each PCSK9 polymorphism was checked and compared by Χ² test. Associations were estimated using odds ratios (OR) and 95% confidence intervals (CI). The potential association between significant PCSK9 polymorphisms and carotid plaques was evaluated by logistic regression. In addition, PCSK9 serum levels were determined by ELISA. All the results were adjusted by sex, age and traditional CV risk factors.

Results: Significant differences in the allele frequencies of rs2495477 between RA patients and controls were found (risk allele: p=0.014, OR=0.55, CI=0.34-0.89). A significant association between risk allele of rs2495477 and carotid plaques was also disclosed in RA patients (p=0.023, OR=0.76, CI=0.59-0.96). PCSK9 protein levels were significant decreased in RA patients carrying rs2495477 risk allele compared to controls (p=0.0001).

Conclusion: Our study shows for the first time a protective role of PCSK9 rs2495477 in a large cohort of RA patients, suggesting this polymorphism as a marker of RA. Furthermore, the risk allele of rs2495477 revealed a protective effect against the development of subclinical atherosclerosis in RA patients. Finally, rs2495477 decrease PCSK9 levels in patients that may be crucial to control RA.

[1] Autoimmun Rev.2016;15:1013-30; [2] Ann Rheum Dis.2014;73:722-7; [3] J Am Coll Cardiol. 2005;45:1611-9; [4] Arthritis Rheum.1988;31:315-24; [5] Arthritis Rheum.2010;62:2569-81.

This study was supported by European Union FEDER funds and “Fondo de Investigación Sanitaria” (PI15/00525) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Program RD16/0012 (RIER) from ISCIII, and by grants from the European IMI BTCure Program. SR-M is supported by RD16/0012/0009 (ISCIII, co-funded by the European Regional Development Fund, ERDF); FG by a Sara Borrell fellowship from ISCIII, co-funded by ESF (CD15/00095); VP-C by funds from IDIVAL (Santander, Spain, PREVAL18/01); VM by a Miguel Servet type I programme (CP16/00033) (ISCIII, co-funded by ERDF); and RL-M is a Miguel Servet type I from ISCIII, co-funded by the European Social Fund, ESF (CP16/00033).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/protective-role-of-the-proprotein-convertase-subtilisin-kexin-type-9-pcsk9-rs2495477-polymorphism-in-patients-with-rheumatoid-arthritis/