Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = -0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves' disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

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Publication Details

Journal
Cell Genomics
Published
2025-03-01
DOI
https://doi.org/10.1016/j.xgen.2025.100783
Citations
7
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
9.77
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Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity

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Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity

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article en
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Abstract

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = -0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves' disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

Cell GenomicsVol. 5(3)
Broad Institute (US), Osaka Gakuin University (JP), Tokyo Medical and Dental University (JP), University of Helsinki (FI), Keio University (JP), Japan Society for the Promotion of Science (JP), Kyoto University (JP), Karolinska Institutet (SE), Juntendo University (JP), Massachusetts General Hospital (US), Fukuoka Tokushukai Hospital (JP), Keio University Hospital (JP), Institute for Molecular Medicine Finland (FI), Aso Iizuka Hospital (JP), RIKEN Center for Integrative Medical Sciences (JP), National Institute of Health Sciences (JP), The University of Tokyo (JP), International University of Health and Welfare (JP), Nippon Medical School (JP), The University of Osaka (JP)
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Openalex Percentile: Top 2%
SARS-CoV-2 and COVID-19 Research
9.77
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