title: Novel insights into systemic autoimmune rheumatic diseases using shared molecular signatures and an integrative analysis.
abstract: We undertook this study to identify DNA methylation signatures of three systemic autoimmune rheumatic diseases (SARDs), namely rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, compared to healthy controls. Using a careful design to minimize confounding, we restricted our study to subjects with incident disease and performed our analyses on purified CD4+T cells, key effector cells in SARD. We identified differentially methylated (using the Illumina Infinium HumanMethylation450 BeadChip array) and expressed (using the Illumina TruSeq stranded RNA-seq protocol) sites between cases and controls, and investigated the biological significance of this SARD signature using gene annotation databases. We recruited 13 seropositive rheumatoid arthritis, 19 systemic sclerosis, 12 systemic lupus erythematosus subjects, and 8 healthy controls. We identified 33 genes that were both differentially methylated and expressed (26 over- and 7 under-expressed) in SARD cases versus controls. The most highly overexpressed gene was CD1C (log fold change in expression = 1.85, adjusted P value = 0.009). In functional analysis (Ingenuity Pathway Analysis), the top network identified was lipid metabolism, molecular transport, small molecule biochemistry. The top canonical pathways included the mitochondrial L-carnitine shuttle pathway (P = 5E-03) and PTEN signaling (P = 8E-03). The top upstream regulator was HNF4A (P = 3E-05). This novel SARD signature contributes to ongoing work to further our understanding of the molecular mechanisms underlying SARD and provides novel targets of interest.
authors.affiliation: a Lady Davis Research Institute , Montréal , QC , Canada.|b Division of Rheumatology , Jewish General Hospital , Montréal , QC , Canada.|c Department of Medicine , McGill University , Montréal , QC , Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Hudson
authors.affiliation: c Department of Medicine , McGill University , Montréal , QC , Canada.|d The Research Institute of the McGill University Health Centre , Montréal , QC , Canada.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bernatsky
authors.affiliation: c Department of Medicine , McGill University , Montréal , QC , Canada.|d The Research Institute of the McGill University Health Centre , Montréal , QC , Canada.
authors.forename: Ines
authors.initials: I
authors.lastname: Colmegna
authors.affiliation: d The Research Institute of the McGill University Health Centre , Montréal , QC , Canada.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Lora
authors.affiliation: e McGill University and Genome Quebec Innovation Centre , McGill University , Montréal , QC , Canada.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: a Lady Davis Research Institute , Montréal , QC , Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Klein Oros
authors.affiliation: a Lady Davis Research Institute , Montréal , QC , Canada.|f Department of Human Genetics , McGill University , Montréal , QC , Canada.|g Department of Oncology , McGill University , Montréal , QC , Canada.|h Department of Epidemiology , Biostatistics & Occupational Health, McGill University , Montréal , QC , Canada.
authors.forename: Celia M T
authors.initials: CMT
authors.lastname: Greenwood
mesh_terms: D000328:Adult; D000368:Aged; D018949:Antigens, CD1 / Q000096:biosynthesis / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006023:Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D012216:Rheumatic Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology
chemical_list: D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: DNA methylation; integrative analysis; systemic autoimmune rheumatic diseases; transcriptome