title: Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells.
abstract: Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.|Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Silva
authors.initials: S
authors.lastname: Kasela
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Kai
authors.identifier: http://orcid.org/0000-0002-5426-4648
authors.initials: K
authors.lastname: Kisand
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Liina
authors.initials: L
authors.lastname: Tserel
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.|Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Epp
authors.identifier: http://orcid.org/0000-0003-4528-3406
authors.initials: E
authors.lastname: Kaleviste
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Anu
authors.initials: A
authors.lastname: Remm
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Krista
authors.identifier: http://orcid.org/0000-0002-3521-0599
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.|Partners Center for Personalized Genetic Medicine, Boston, MA, United States of America.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States of America.
authors.forename: Harm-Jan
authors.identifier: http://orcid.org/0000-0001-7038-567X
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.|Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Lili
authors.identifier: http://orcid.org/0000-0002-5323-3102
authors.initials: L
authors.lastname: Milani
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002874:Chromosome Mapping / Q000379:methods; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D064094:Interleukin-27 / Q000235:genetics; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D064094:Interleukin-27; C489203:RPS26 protein, human; D012269:Ribosomal Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human