Age and Sex Specific Modulation of Serum Proprotein Convertase Subtilisin/kexin type 9 Levels in Rheumatoid Arthritis

Abstract

Background/PurposeProprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that regulates cholesterol homeostasis by inducing posttranslational modification and lysosomal degradation of low‐density lipoprotein receptor (LDLR). However, the role of PCSK9 in dyslipidemia associated with rheumatoid arthritis (RA) is not well studied. The aim of this study was to examine how PCSK9 levels correlate with age [30–45; 46–60; and 61–80 years], sex, and RA disease, and with CD36, a major scavenger receptor targeted for proteasomal degradation by PCSK9.MethodsDe‐identified human RA serum samples (n=66; 33 female and 33 male) were obtained from patients diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and healthy, age and gender‐matched serum samples were used for evaluation. Serum levels of human PCSK9 and CD36 were determined using commercially available ELISA kits.ResultsThe mean (SD) age of healthy group [55.6 (11.2) years] and RA group [57.2 (10.4) years] was observed. Results of the ELISA showed that the serum levels of PCSK9 in RA group is reduced by ~10% (mean ± SEM; 231 ± 11.6 ng/ml vs. 205 ± 11.1 ng/ml; p<0.14). Interestingly, our gender‐based analysis showed that the basal serum PCSK9 levels were around 30% higher in the healthy female group compared to the healthy male group (260 ± 15.9 ng/ml vs. 202 ± 15.4 ng/ml; p=0.01). Furthermore, from a disease perspective, we observed approximately 15% lower serum PCSK9 levels in female RA group (260 ± 15.9 ng/ml vs. 219 ± 14.4 ng/ml; p=0.078) compared to only a modest 5% decline in male RA group (202 ± 15.4 ng/ml vs. 191 ± 16.8 ng/ml; p=0.62) when compared to their respective gender control groups. Analysis of PCSK9 data based on age showed that while PCSK9 levels gradually decreased in healthy female group [274.4 ± 38.9 ng/ml in 30–45y range vs. 241 ± 20.7 ng/ml in 61–80y], we observed an accelerated decrease in serum PCSK9 levels in RA female group [278.5 ± 62.4 ng/ml in 30–45y range vs. 220 ± 19.2 ng/ml in 46–60y; p=0.14]. This suggests that PCSK9 levels rapidly decline with RA progression in aging females. Interestingly, the serum PCSK9 levels in both healthy and RA male groups showed declines at a later stage of life [61–80y range; p<0.001], implicating that PCSK9 levels deplete in male groups, independent of RA disease pathogenesis. Serum CD36 levels in healthy female group were modestly low when compared to the serum levels in healthy male group [mean ± SEM; 1121 ± 164 pg/ml vs. 1280 ± 216 pg/ml; p<0.562]. Interestingly, while the CD36 levels were around 30% higher in RA males compared to the healthy male controls, we observed a modest decrease in serum CD36 by 15–20% in RA females when compared to the healthy female controls.ConclusionOur findings provide evidence of the gender differences in serum PCSK9 levels and its modulation with age. Furthermore, it is speculated that an early decline in serum PCSK9 in female RA patients may contribute towards the establishment of RA in females.Support or Funding InformationWashington State University, Spokane, WAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.