Characterization of PCSK9 in the Blood and Skin of Psoriasis

Mechanisms explaining the link between psoriasis, a pro-inflammatory condition, and cardiovascular disease (CVD) are not fully known. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism and clinical trials targeting PCSK9 reduce CVD. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict CV events. We used two separate human psoriasis cohorts and the K14-Rac1V12-/+ murine model of psoriasis to investigate PCSK9 and CV risk in psoriasis. In both psoriasis cohorts, (n=88 and n=20), PCSK9 levels were 20% and 13% higher than age, sex, and cholesterol matched controls respectively (p<0.05 for each comparison), and correlated with psoriasis area severity index (r=0.43, p<0.05). Despite no difference in hepatocyte expression, K14-Rac1V12-/+ mice demonstrated skin-specific PCSK9 staining which was confirmed in human psoriatic lesional skin. In psoriasis patients, PCSK9 levels correlated with impaired endothelial vascular health (e.g. early atherosclerosis, β=4.5, p<0.01) and coronary artery calcium score (β=0.30, p=0.01) which remained significant after adjustment for Framingham risk, body mass index and active biologic use. Taken together, these findings suggest independent of cholesterol, an association between circulating PCSK9, and early and advanced stages of atherosclerosis in psoriasis.