title: Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses.
abstract: The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany. Electronic address: christian.hammer@epfl.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Hammer
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Begemann
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaren
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: István
authors.initials: I
authors.lastname: Bartha
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Infections and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Michel
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Klose
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Infections and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Waterboer
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, Infections and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: Institute of Virology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, 37075 Göttingen, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D016867:Immunocompromised Host / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011487:Protein Conformation; D012559:Schizophrenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology* / Q000821:virology; D014780:Viruses / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G