RT Journal Article
T1 Epigenome-Wide Comparative Study Reveals Key Differences Between Mixed Connective Tissue Disease and Related Systemic Autoimmune Diseases.
A1 Carnero-Montoro, Elena
A1 Barturen, Guillermo
A1 Povedano, Elena
A1 Kerick, Martin
A1 Martinez-Bueno, Manuel
A1 PRECISESADS Clinical Consortium, 
A1 Ballestar, Esteban
A1 Martin, Javier
A1 Teruel, María
A1 Alarcón-Riquelme, Marta E
K1 biomarker
K1 epigenetics
K1 genome-wide DNA methylation
K1 interferon
K1 meQTL
K1 mixed connective tissue disease
K1 systemic autoimmunity
AB Mixed Connective Tissue Disease (MCTD) is a rare complex systemic autoimmune disease (SAD) characterized by the presence of increased levels of anti-U1 ribonucleoprotein autoantibodies and signs and symptoms that resemble other SADs such as systemic sclerosis (SSc), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Due to its low prevalence, this disease has been very poorly studied at the molecular level. We performed for the first time an epigenome-wide association study interrogating DNA methylation data obtained with the Infinium MethylationEPIC array from whole blood samples in 31 patients diagnosed with MCTD and 255 healthy subjects. We observed a pervasive hypomethylation involving 170 genes enriched for immune-related function such as those involved in type I interferon signaling pathways or in negative regulation of viral genome replication. We mostly identified epigenetic signals at genes previously implicated in other SADs, for example MX1, PARP9, DDX60, or IFI44L, for which we also observed that MCTD patients exhibit higher DNA methylation variability compared with controls, suggesting that these sites might be involved in plastic immune responses that are relevant to the disease. Through methylation quantitative trait locus (meQTL) analysis we identified widespread local genetic effects influencing DNA methylation variability at MCTD-associated sites. Interestingly, for IRF7, IFI44 genes, and the HLA region we have evidence that they could be exerting a genetic risk on MCTD mediated through DNA methylation changes. Comparison of MCTD-associated epigenome with patients diagnosed with SLE, or Sjögren's Syndrome, reveals a common interferon-related epigenetic signature, however we find substantial epigenetic differences when compared with patients diagnosed with rheumatoid arthritis and systemic sclerosis. Furthermore, we show that MCTD-associated CpGs are potential epigenetic biomarkers with high diagnostic value. Our study serves to reveal new genes and pathways involved in MCTD, to illustrate the important role of epigenetic modifications in MCTD pathology, in mediating the interaction between different genetic and environmental MCTD risk factors, and as potential biomarkers of SADs.
YR 2019
FD 2019-08-07
LK http://hdl.handle.net/10668/14434
UL http://hdl.handle.net/10668/14434
LA en
DS RISalud
RD Apr 6, 2025