Protective role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) RS2495477 polymorphism in patients with rheumatoid arthritis and subclinical atherosclerosis

Abstract

Background: RA is associated with the development of cardiovascular (CV) disease and subclinical atherosclerosis1. 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 atherosclerosis1,3. PCSK9 polymorphisms can both increase and decrease the risk of CV disease in patients with atherosclerosis3. Moreover, PCSK9 levels have been also related with CV risk4. However, there is little information on PCSK9 in RA.

Objectives: To assess the role of several PCSK9 polymorphisms in RA and subclinical atherosclerosis in RA as well as to determine if these ones may influence on PCSK9 mRNA and protein levels.

Methods: PCSK9 rs2479409, rs11583680, rs2483205, rs2495477 and rs562556 polymorphisms were genotyped in 1,169 Spanish RA patients, who met the 1987 ACR and the 2010 ACR/EULAR criteria for RA5-6, and 528 healthy controls. Associations were estimated using odds ratios (OR) and 95% confidence intervals (CI). The potential association between PCSK9 polymorphisms in both RA and controls and the presence/absence of carotid plaques in RA was evaluated by logistic regression. PCSK9 mRNA expression and PCSK9 serum levels were determined by qPCR and ELISA, respectively. All results were adjusted by sex, age and traditional CV risk factors.

Results: Significant differences in the allele frequencies of PCSK9 rs2495477 between RA patients and controls were found (minor allele: OR=0.55, 95% CI=0.34-0.89, p=0.01). A significant association between minor allele of rs2495477 and carotid plaques was also disclosed in RA patients (OR=0.72, 95% CI=0.56-0.92, p=0.01). PCSK9 levels were significantly decreased in RA patients carrying rs2495477 minor allele compared to controls (97.8 ± 104.9 vs 235.8 ± 93.5 ng/mL, p=0.001). None of the five PCSK9 polymorphisms influenced on its expression.

Conclusion: Our study showed for the first time that PCSK9 rs2495477 confers protection against RA susceptibility and the development of subclinical atherosclerosis in RA patients. Furthermore, rs2495477 decreased PCSK9 serum levels in RA that may be crucial to control the disease.