Session Type: Abstract Session
Session Time: 4:00PM-4:50PM
Background/Purpose: 1. To develop integrated analyses of the genome-wide DNA methylation and gene expression profiles in monocytes from APS patients and assess their involvement in cardiovascular pathology. 2. To evaluate the role of antiphospholipid antibodies (aPL) in the regulation of these processes.
Methods: Thirty-three APS patients were included in the study. Monocytes were isolated from peripheral blood by positive immunomagnetic selection. The Illumina Infinium Methylation EPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs. Total RNA was processed for sequencing library preparation using 75bp paired-end NextGen sequencing (Illumina NextSeq 500 instrument). To examine the impact of DNA methylation on the local regulation of gene expression, the Pearson correlation (r) was calculated between the beta values (β) of CpGs located in promoter regions and the normalized expression values of the corresponding genes. Functional classification of these genes was carried out by gene ontology analysis. Gene expression of selected genes was evaluated by RT-PCR. CV-risk parameters were further assessed, and correlation/association studies were developed with clinical/analytical variables. The effects of aPLs were also evaluated by in vitro studies.
Results: Integrative analysis of DNA methylation and gene expression identified 4727 mRNAs whose expression was linked to methylation levels. Functional classification of these genes revealed signatures associated with biological processes and pathways related to immune response, adhesion, oxidative stress and vascular signaling. Thus, correlation and association studies showed that altered mRNA expression of several genes whose altered expression was linked to aberrant methylation levels were further related to the CV-risk score, -aGAPSS- (TGFB1, SERPINB6, NFKB1, SLC25A24, IFNAR2, CXCL8, SOD2), the vascular involvement -type of thrombosis and thrombotic recurrences- (IFI52, IL18BP, IL6R, ITGA5, SLC25A26, STAT5A) and the microvascular endothelial dysfunction (HLA-DPA1, SLS25A26,SLC25A45, SERPINB9). Abnormal methylation and transcription levels of several genes were further associated with a pathological increase of the CIMT.
Lastly, expression levels of several genes related to cytokine-mediated signaling pathway, oxidative stress and mitochondrial dysfunction (PLXND1, CXCR4, PDE4A, TNFRSF1A, IL17RA, MMP17, CXXC1, IL10RA, TNFRSF1B, SERPINB6, NFKB2, SFPQ, ILF3, STAT5A, JAK2) correlated with aPL titers. In vitro studies further supported the role of aPLs as key players in the altered methylation and transcriptomic profiles of APS patients.
Conclusion: APS patients showed coordinately impaired methylation and gene expression profiles in monocytes of genes associated with clinical features of the disease such as autoantibody titers, CV risk score -aGAPSS-, thrombotic recurrences and early atherosclerosis. These results offered a map to the monocytes methylome and their influence on gene expression, and shed light on the pathophysiology of APS, paving the way for the development of effective biomarkers and therapeutics.
Funded by ISCIII (PI18/0837 and RIER RD16/0012/0015) co-funded with FEDER.
To cite this abstract in AMA style:Pérez-Sánchez C, Aguirre M, Patiño-Trives A, Pérez-Sanchez L, Luque-Tevar M, Arias de la Rosa I, Abalos-Aguilera M, Segui P, Rodriguez-Ubreva J, Ballestar E, Barbarroja N, Collantes-Estévez E, Lopez-Pedrera C. Integrative Analysis of DNA Methylation and Gene Expression in Monocytes from Primary Antiphospholipid Syndrome Patients Identifies a Gene Expression Signature Associated with Their Atherothrombotic Phenotype [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/integrative-analysis-of-dna-methylation-and-gene-expression-in-monocytes-from-primary-antiphospholipid-syndrome-patients-identifies-a-gene-expression-signature-associated-with-their-atherothrombotic-p/. Accessed November 25, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/integrative-analysis-of-dna-methylation-and-gene-expression-in-monocytes-from-primary-antiphospholipid-syndrome-patients-identifies-a-gene-expression-signature-associated-with-their-atherothrombotic-p/