Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses

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 associ...

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Bibliographic Details
Published in:	American journal of human genetics Vol. 97; no. 5; pp. 738 - 743
Main Authors:	Hammer, Christian, Begemann, Martin, McLaren, Paul J., Bartha, István, Michel, Angelika, Klose, Beate, Schmitt, Corinna, Waterboer, Tim, Pawlita, Michael, Schulz, Thomas F., Ehrenreich, Hannelore, Fellay, Jacques
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-11-2015 Cell Press Elsevier
Subjects:	Adult Amino acids Antigens Autoimmune diseases Autoimmune Diseases - genetics Autoimmune Diseases - immunology Autoimmune Diseases - pathology Biological variation Case-Control Studies Female Follow-Up Studies Genetics Genome-Wide Association Study Histocompatibility Antigens Class II - chemistry Histocompatibility Antigens Class II - genetics Histocompatibility Antigens Class II - immunology Humans Immunity, Humoral - immunology Immunocompromised Host - immunology Immunoglobulin G - blood Immunoglobulins Male Polymorphism, Single Nucleotide - genetics Prognosis Protein Conformation Schizophrenia - genetics Schizophrenia - immunology Schizophrenia - pathology Virus Diseases - genetics Virus Diseases - immunology Virus Diseases - virology Viruses - immunology
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	0002-9297 1537-6605
DOI:	10.1016/j.ajhg.2015.09.008