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

Christian Hammer,Martin Begemann,Paul J Mclaren,István Bartha,Angelika Michel,Beate Klose,Corinna Schmitt,Tim Waterboer,Michael Pawlita,Thomas F Schulz,Hannelore Ehrenreich,Jacques Fellay

doi:10.1016/j.ajhg.2015.09.008

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.

Highlights

The humoral immune response plays an essential role in the control and prevention of viral infections in humans
It has long been known that concentrations of serum immunoglobulins vary from person to person,[1] and antibody titers against prevalent viruses have been shown to be highly variable in the population.[2,3]
To investigate the impact of common human genetic variation on humoral immunity and to identify pathogen-specific variants associated with antibody response, we measured serum immunoglobulin G (IgG) levels against 14 common viruses (Table 1) in 2,363 immunocompetent adults of European ancestry (Figure S1) with available genome-wide genotype data,[4] comprising 1,147 anonymized blood donors (62.0% male, mean age 5 SD 1⁄4 37.5 5 13.2) and 1,216 individuals with psychiatric diagnoses (64.9% male, mean age 5 SD 1⁄4 40.6 5 13.5) who were recruited for the Gottingen Research Association for Schizophrenia (GRAS).[5,6]

Summary

REPOR T

Christian Hammer,1,2,3,* Martin Begemann,[3] Paul J. To investigate the impact of common human genetic variation on humoral immunity and to identify pathogen-specific variants associated with antibody response, we measured serum immunoglobulin G (IgG) levels against 14 common viruses (Table 1) in 2,363 immunocompetent adults of European ancestry (Figure S1) with available genome-wide genotype data,[4] comprising 1,147 anonymized blood donors (62.0% male, mean age 5 SD 1⁄4 37.5 5 13.2) and 1,216 individuals with psychiatric diagnoses (64.9% male, mean age 5 SD 1⁄4 40.6 5 13.5) who were recruited for the Gottingen Research Association for Schizophrenia (GRAS).[5,6] All study participants provided informed consent, including consent for genetic testing, and the GRAS data collection has been approved by the ethical committee of the Georg-August-Universitat Gottingen as well as by the respective local regulatories and ethical committees of all collaborating centers.[6] All subject data were collected in accordance with ethical guidelines and the Helsinki Declaration.[7].

JC polyomavirus

Amino acid

Findings

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