Background:Cardiovascular risk factors are increased in Psoriatic Arthritis (PsA). In fact, around 60% out of PsA patients display insulin resistance (IR), a hallmark of metabolic syndrome, which might significantly contribute to the cardiovascular disease. Latest studies suggested that inflammatory and metabolic disorders may be under epigenetic control, including DNA methylation. DNA methylation is an unexplored area in the field of PsA.Objectives:To study the alterations in the genome-wide DNA methylation profile of CD4+T cells from PsA patients and its relationship with its pathology and the risk of cardiovascular comorbidity.Methods:Twenty healthy controls (HC) and 20 PsA patients were included in the study. PsA patients were classified into insulin resistant and non-insulin resistant according to HOMA-IR index. CD4+T lymphocytes were isolated from peripheral blood by positive immunomagnetic selection. The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs (TSS1500, TSS200, 5UTR, 3UTR, first exon, gene body). Beta values (β) estimating methylation levels were obtained at each CpG site, and differentially methylated genes (DMG) between PsA and HC were identified. Functional classification of these genes was carried out through gene ontology analysis (PANTHER database). Gene expression analysis of the selected genes was also evaluated by RT-PCR. Vascular parameters including carotid intima-media thickness (cIMT) and endothelial function was analyzed by ecodoppler and periflux respectively.Results:The genome-wide methylation analysis identified 112 DMGs including 41 hypomethylated and 71 hypermethylated. These differentially methylated genes were enriched with several signaling pathways and disease categories including immune response, metabolic processes, oxidative stress, vascular and inflammatory pathways. The altered gene expression of selected genes with altered methylation levels in PsA was also validated. Correlation and association analysis of these DMGs with clinical and analytical variables, cardiovascular risk factors and endothelial microvascular function revealed that the degree of methylation of these genes was significantly associated with cIMT (IGF1R, NDRG3, SMYD3, HLA-DRB1, WDR70), arterial pressure (METT5D1, NRDG3, ADAM17, SMYD3, WNK1, CBX1), insulin resistance (AKAP13, SEMA6D, PLCB1), altered lipid profile and atherogenic index (MYBL1, METT5D1, MAN2A1, SLC1A7, SEMA6D, PLCB1, TLK1, SDK1, CBX1), inflammation (MYBL1, NDUFA5, METT5D1, SEMA6D, PLCB1, TLK1), and endothelial dysfunction (ADAMST10, GPCPD1, CCDC88A). In addition, this analysis also identified 435 DMGs including 280 hypomethylated and 155 hypermethylated in CD4+T cells from IR-PsA vs non IR-PsA patients. Between these two groups of PsA patients, CHUK, SERINC1, RUNX1, TTYH2, TXNDC11, FAF1, BICD1, SCD5, PDE5A, FAS, NFIA and GRP75 displayed the most significantly altered methylation, suggesting the role of these genes in the metabolic complications associated with PsA.Conclusion:These findings help our understanding of the pathogenesis of PsA and advance epigenetic studies in regards to this disease and the cardiometabolic comorbidities associated. Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:Iván Arias de la Rosa: None declared, María Dolores López Montilla Speakers bureau: Celgene, Javier Rodríguez: None declared, Esteban Ballester: None declared, Carmen Torres-Granados: None declared, Carlos Perez-Sanchez: None declared, Maria del Carmen Abalos-Aguilera: None declared, Gómez García Ignacio: None declared, Desiree Ruiz: None declared, Alejandra M. Patiño-Trives: None declared, María Luque-Tévar: None declared, Eduardo Collantes-Estévez Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Alejandro Escudero Contreras Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene.
Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients