title: Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells.
abstract: Genome-wide association studies (GWAS) and subsequent dense-genotyping of associated loci identified over a hundred single-nucleotide polymorphism (SNP) variants associated with the risk of rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CeD). Immunological and genetic studies suggest a role for CD4-positive effector memory T (CD+ TEM) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4+ effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4+ TEM cells from peripheral blood, then assayed relative abundance, proliferation upon T cell receptor (TCR) stimulation, and the transcription of 215 genes within disease loci before and after stimulation. We identified 46 genes regulated by cis-acting expression quantitative trait loci (eQTL), the majority of which we detected in stimulated cells. Eleven of the 46 genes with eQTLs were previously undetected in peripheral blood mononuclear cells. Of 96 risk alleles of RA, T1D, and/or CeD in densely genotyped loci, eleven overlapped cis-eQTLs, of which five alleles completely explained the respective signals. A non-coding variant, rs389862A, increased proliferative response (p=4.75 × 10-8). In addition, baseline expression of seventeen genes in resting cells reliably predicted proliferative response after TCR stimulation. Strikingly, however, there was no evidence that risk alleles modulated CD4+ TEM abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants.
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America; Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, United States of America.
authors: Xinli
authors: X
authors: Hu
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America.
authors: Hyun
authors: H
authors: Kim
authors: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Towfique
authors: T
authors: Raj
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Patrick J
authors: PJ
authors: Brennan
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors: Gosia
authors: G
authors: Trynka
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Nikola
authors: N
authors: Teslovich
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Kamil
authors: K
authors: Slowikowski
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Wei-Min
authors: WM
authors: Chen
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Suna
authors: S
authors: Onengut
authors: Department of Dermatology/Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Clare
authors: C
authors: Baecher-Allan
authors: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Philip L
authors: PL
authors: De Jager
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Stephen S
authors: SS
authors: Rich
authors: Section of Genetic Medicine, University of Chicago, Chicago, Illinois, United States of America; Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America.
authors: Barbara E
authors: BE
authors: Stranger
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Michael B
authors: MB
authors: Brenner
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors: Soumya
authors: S
authors: Raychaudhuri
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002446:Celiac Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics
chemical_list: D011948:Receptors, Antigen, T-Cell