An inflammatory transcriptomic signature in psoriasis associates with future cardiovascular events

Abstract

Background: Psoriasis is an inflammatory skin disease associated with increased cardiovascular (CV) risk, whose pathogenesis is not fully known.

Objective: We identified a transcriptomic signature in psoriasis and investigated its association with prevalent and future risk of a CV event to understand the connection between psoriasis and CV disease (CVD).

Methods: Psoriasis patients (n = 37) with a history of moderate-severe skin disease without CVD and 11 matched controls underwent whole blood RNA sequencing. This transcriptomic signature in psoriasis versus controls was evaluated in two CVD cohorts: Women referred for cardiac catheterization with (n = 76) versus without (n = 97) myocardial infarction (MI), and patients with peripheral artery disease (n = 106) followed over 2.5 years for major adverse CV or limb events (MACLE). The association between genes differentially expressed in psoriasis and prevalent and incident CV events was assed.

Results: In psoriasis, median age was 44 (IQR; 34-51) years, 49% male and ACC/AHA ASCVD Risk Score of 1.0% (0.6-3.4) with no significant difference versus controls. The median psoriasis area and severity index score (PASI) was 4.0 (IQR 2.9-8.2) with 36% on biologic therapy. Overall, 247 whole blood genes were upregulated and 228 downregulated in psoriasis versus controls (p < 0.05), and 1302 genes positively and 1244 genes negatively correlated with PASI (p < 0.05). Seventy-three genes overlapped between psoriasis prevalence and PASI with key regulators identified as IL-6, IL-1β and interferon gamma. In the CVD cohorts, 50 of 73 genes (68%) identified in psoriasis associated with prevalent MI, and 29 (40%) with incident MACLE. Key regulator transcripts identified in psoriasis and CVD cohorts included SOCS3, BCL3, OSM, PIM2, PIM3 and STAT5A.

Conclusions: A whole blood transcriptomic signature of psoriasis diagnosis and severity associated with prevalent MI and incident MACLE. These data have implications for better understanding the link between psoriasis, systemic inflammation and CVD.

Figure 1:. A circulating transcriptomic signature in psoriasis centers around pro-inflammatory processes.

A) Study design and volcano plot (nominal p<0.05), B) Heat map of top differentially expressed genes (nominal p<0.01), C) Top differentially expressed canonical pathways, and D) Enriched cytokine regulators of whole blood gene expression comparing psoriasis (n=37) to controls (N=11). E) Study design and volcano plot (nominal p<0.05) and F) Enriched cytokine regulators of differentially expressed blood transcripts assessing the association between psoriasis area and severity index and whole blood gene expression (nominal p<0.05). G) Overlap in upregulated and downregulated gene expression (genes = 73) between psoriasis vs. control (A) and association between psoriasis severity and whole blood gene expression (E). Enriched cytokine H) and transcript regulators I) of gene overlap from G. All pathways assessed using Ingenuity Pathway Analysis with differential gene expression adjusted for age, gender, body mass index, and active biologic use.

Figure 2.. A circulating transcriptomic signature in psoriasis associates with prevalent and future cardiovascular events.

A) Heat map (Log₂ fold change) of differential expressed psoriasis genes (vs. control) identified in Figure 1G also upregulated in a cohort of women (HARP cohort) referred for a coronary angiogram with myocardial infarction (MI) versus controls without MI, and a second cohort of patients with established cardiovascular disease (PACE-cohort, peripheral artery disease) at baseline followed longitudinally for a major adverse cardiovascular or limb event (MACLE) over a median follow-up of 2.5 years (all nominal p<0.05). Cytokine and transcription regulators of differentially expressed genes (nominal p<0.05) from Figure 2A in the HARP cohort B), and the PACE cohort C). D) Individual genes which compile cytokine and transcript regulator analyses from Ingenuity Pathway Analysis. E) Individual transcripts of those that did (MI) vs did not (controls) have an acute MI in HARP cohort (t-test). F) Kaplan-Meier curve and log-rank P value for select genes and the outcome of MACE in PACE cohort. HARP: Women’s Heart Attack Research Program. MACE/MACLE: Major adverse cardiovascular (or limb) events. MI; Myocardial infarction. NCV; Normalized count value. PACE; Platelet Activity and Vascular Surgery and cardiovascular events. (Mann-Whitney U-test) *<0.05, **<0.01, ***<0.001.