Nucleic Acid-Sensing and Interferon-Inducible Pathways Show Differential Methylation in MZ Twins Discordant for Lupus and Overexpression in Independent Lupus Samples: Implications for Pathogenic Mechanism and Drug Targeting.

Autor:	Marion MC; Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.; Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Ramos PS; Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA., Bachali P; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA., Labonte AC; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA., Zimmerman KD; Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Ainsworth HC; Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.; Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Heuer SE; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA.; The Jackson Laboratory, Tufts Graduate School of Biomedical Sciences, Bar Harbor, ME 04609, USA., Robl RD; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA., Catalina MD; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA., Kelly JA; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA., Howard TD; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Lipsky PE; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA., Grammer AC; AMPEL BioSolutions, LLC and RILITE Research Institute, Charlottesville, VA 22902, USA., Langefeld CD; Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.; Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Jazyk:	angličtina
Zdroj:	Genes [Genes (Basel)] 2021 Nov 26; Vol. 12 (12). Date of Electronic Publication: 2021 Nov 26.
DOI:	10.3390/genes12121898
Abstrakt:	Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant for SLE. Genes implicated by the epigenetic analyses were then evaluated in 10 independent SLE gene expression datasets from the Gene Expression Omnibus (GEO). There were 59 differentially methylated loci between unaffected and affected MZ twins in whole blood, including 11 novel loci. All but two of these loci were hypomethylated in the SLE twins relative to the unaffected twins. The genes harboring these hypomethylated loci exhibited increased expression in multiple independent datasets of SLE patients. This pattern was largely consistent regardless of disease activity, cell type, or renal tissue type. The genes proximal to CpGs exhibiting differential methylation (DM) in the SLE-discordant MZ twins and exhibiting differential expression (DE) in independent SLE GEO cohorts (DM-DE genes) clustered into two pathways: the nucleic acid-sensing pathway and the type I interferon pathway. The DM-DE genes were also informatically queried for potential gene-drug interactions, yielding a list of 41 drugs including a known SLE therapy. The DM-DE genes delineate two important biologic pathways that are not only reflective of the heterogeneity of SLE but may also correlate with distinct IFN responses that depend on the source, type, and location of nucleic acid molecules and the activated receptors in individual patients. Cell- and tissue-specific analyses will be critical to the understanding of genetic factors dysregulating the nucleic acid-sensing and IFN pathways and whether these factors could be appropriate targets for therapeutic intervention.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu