Abstract
Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.
Highlights
The variability of the humoral response to antigenic stimulation has been documented for a long time (Grundbacher 1974)
We observed a significant decrease with age in antibody levels against BK polyomavirus (BKPyV) (P < 2 × 10−16), JC polyomavirus (JCPyV) (P = 4.56 × 10−03), Merkel cellpolyomavirus (MCPyV) (P = 5.77 × 10−03), and WU polyomavirus (WUPyV) (P < 2 × 10−16) and lower immunoglobulin G (IgG) levels against human polyomavirus 6 (HPyV6) (P = 3.51 × 10−15), JCPyV (P < 2 × 10−16), and MCPyV (P = 1.07 × 10−05) in female participants
We performed a total of nine independent genome-wide association study (GWAS) using either a case–control study design or a continuous, quantitative approach (IgG levels in seropositive individuals) to search for human genetic determinants of the antibody response to BKPyV and JCPyV in the three cohorts, to HPyV6 and WUPyV in Cohorte Lausannoise (CoLaus) and Gottingen Research Association for Schizophrenia (GRAS), and to MCPyV in GRAS and UK Biobank (UKB) (Fig. 1)
Summary
The variability of the humoral response to antigenic stimulation has been documented for a long time (Grundbacher 1974). Human genetic factors were estimated to account for 35 per cent (±6 per cent) and 21 per cent (±5 per cent) of the variance in Helicobacter pylori and Toxoplasma gondii antibody levels and 60 per cent (±11 per cent) and 57 per cent (±11 per cent) of the variance in cytomegalovirus and Epstein–Barr virus (EBV) serostatus, respectively (Rubicz et al 2011). This high heritability makes serological phenotypes highly promising targets for human genomic studies. This highly polymorphic complex notably encodes the class I and class II human leukocyte antigen (HLA) proteins, which present antigenic epitopes to effector cells of the immune system—a key role in the crossroad between innate and acquired immune responses
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