Background/Purpose: Traditional cardiovascular disease (CVD) risk factors could be underestimating the subclinical atherosclerosis in patients with Spondyloarthritis (SpA). The identification of subclinical CVD sings and its molecular drivers, such as epigenetic regulators, acquires relevance. The aim of this work is to identify potential CVD biomarkers based on proteomic and epigenomic data, and its relation with clinical features in SpA.

Methods: A cross-sectional study was performed in 95 patients with SpA compared to 31 healthy donors (HDs). Disease activity and CVD risk factors was determined. Structural damage was evaluated using mSASSS was analyzed. Levels of 92 CVD-related proteins were determined in plasma using Olink technology (Uppsala, Sweden). Blood genome-wide DNA methylation at more than 800,000 CpG sites was measured using the Illumina MethylationEPIC array. Association studies of CVD-related proteins and epigenetic modifications at their protein-coding genes with SpA clinical aspects were performed.

Results: Patients with SpA presented higher prevalence of CVD comorbidities compared to HDs. As much as 20% of SpA patients showed atherosclerotic plaques. SpA patients showed significant elevated circulating levels of 12 CVD-related proteins compared to HDs. Among them, MMP9, UPAR, PGLYRP1, RARRES2, PDGFA and CHI3L1 were significantly associated with acute phase reactants, whereas GDF15 was related to mSASS. GDF15, MMP9 and CTSB were associated with hypertension. GDF15 and CTSB were associated with uveitis and CHI3L1, CTSB, GDF15, TNFR1 and CTSD with hyperuricemia. Interestingly, patients with atherosclerotic plaques showed significant higher levels of CTSB, IL2RA, GDF15 compared to those without plaques. Among them, levels of GDF15 and CTSB could distinguish patients with atherosclerotic plaques with a high accuracy (AUC=0.80 and AUC=0.72, respectively). On the other hand, we identified DNA methylation levels within 81 CpG sites associated with circulating CVD-related proteins. Methylation of GDF-15 and CTSB genes in whole blood significantly correlated to the plasma levels of those proteins. In addition, GDF-15 and CTSB methylation was directly related to the presence of atherosclerotic plaques and exhibited a high predictive value (AUC=0.84). The combining information on GDF-15 and CTSB circulating levels and whole-blood DNA methylation was the best marker to identify patients with atherosclerotic plaques (AUC=0.93)

Conclusion: 1) SpA patients present an altered CVD proteome profile that is associated with CVD comorbidities and clinical aspects of the disease; 2) DNA methylation patterns and levels of GDF15 and CTSB could be use as potential subclinical CVD biomarkers; 3) epigenetic markers boost the predictive ability and can harbor additional information about underlying biological process in the process of atherosclerotic plaque formation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cardiovascular-disease-proteome-profile-is-related-to-an-abnormal-methylome-pattern-in-spondyloarthritis-potential-biomarkers-of-subclinical-atherosclerosis/