title: Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms.
abstract: Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes using a gene-gene interaction network, and place the genetic risk loci in the context of the intrinsic subsets. To identify gene expression modules common to three independent datasets from three different clinical centers, we developed a consensus clustering procedure based on mutual information of partitions, an information theory concept, and performed a meta-analysis of these genome-wide gene expression datasets. We created a gene-gene interaction network of the conserved molecular features across the intrinsic subsets and analyzed their connections with SSc-associated genetic polymorphisms. The network is composed of distinct, but interconnected, components related to interferon activation, M2 macrophages, adaptive immunity, extracellular matrix remodeling, and cell proliferation. The network shows extensive connections between the inflammatory- and fibroproliferative-specific genes. The network also shows connections between these subset-specific genes and 30 SSc-associated polymorphic genes including STAT4, BLK, IRF7, NOTCH4, PLAUR, CSK, IRAK1, and several human leukocyte antigen (HLA) genes. Our analyses suggest that the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically interconnected and related to a patients underlying genetic risk.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Mahoney
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Taroni
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: Viktor
authors.initials: V
authors.lastname: Martyanov
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: Tammara A
authors.initials: TA
authors.lastname: Wood
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: Casey S
authors.initials: CS
authors.lastname: Greene
authors.affiliation: Department of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pioli
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Hinchcliff
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hannover, New Hampshire, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
mesh_terms: D000368:Aged; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012306:Risk; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D059467:Transcriptome / Q000235:genetics*