title: Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli.
abstract: The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Housley
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Salvador D
authors.initials: SD
authors.lastname: Fernandez
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Vera
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Sasidhar R
authors.initials: SR
authors.lastname: Murikinati
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Grutzendler
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cuerdon
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Glick
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Mitja
authors.initials: M
authors.lastname: Mitrovic
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Genetics, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Cotsapas
authors.affiliation: Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. david.hafler@yale.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000367:Age Factors; D000483:Alleles; D015551:Autoimmunity / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D021381:Protein Transport; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D012307:Risk Factors; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha