| Title: |
Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity |
| Authors: |
BioBank Japan Project; Japan COVID-19 Task Force; Sonehara, Kyuto; Uwamino, Yoshifumi; Saiki, Ryunosuke; Nakanishi, Tomoko; Liu, Aoxing; Hara, Akemi |
| Contributors: |
Institute for Molecular Medicine Finland; Data Science Genetic Epidemiology Lab; University of Helsinki; Helsinki Institute of Life Science HiLIFE |
| Publisher Information: |
Cell Press |
| Publication Year: |
2025 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
clonal hematopoiesis; COVID-19 vaccine; genome-wide association study; Graves’ disease; immunogenicity; immunoglobulin heavy chain; major histocompatibility complex; mosaic chromosomal alteration; mosaic loss of chromosome X; mosaic loss of chromosome Y; sepsis; Biomedicine; General medicine; internal medicine and other clinical medicine |
| Description: |
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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
We would like to thank all the participants involved in this study. We sincerely thank Dr. Michiaki Kubo and the members of the RIKEN Center for Integrative Medical Sciences for their support of this study. We thank all the participants involved in this study and all the members of the JCTF for their support. We thank J. Kitano, the e-Parcel Corporation, and the Ascend Corporation for supporting the JCTF. This research was supported by the KAKENHI Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) (grant nos. 23K14451 [to K.S.] and 22H00476 [to Y. Okada]); the Japan Agency for Medical Research and Development (AMED) (grant nos. JP23fk0108686 [to Y.U.]; JP21fk0108469 and JP24tm0524008 [to H.N.]; and JP24km0405217, JP24ek0109594, JP24ek0410113, JP24kk0305022, JP243fa627002, JP243fa627010, JP243fa627011, JP24zf0127008, JP24tm0524002, JP24wm0625504, and JP24gm1810011 [to Y. Okada]); JST Moonshot R&D (grant nos. JPMJMS2021 and JPMJMS2024 [to Y. Okada]); JST PRESTO (grant nos. JPMJPR21R7 [to H.N.], JPMJPR22R2 [to Y.U.], Keio University Academic Development Fund [Joint Research] [to H.N.], the Japan Prize Foundation [to H.N.], and Public Foundation of Vaccination Research Center [to Y.U.]; the Takeda Science Foundation; the Ono Pharmaceutical Foundation for Oncology, Immunology, and Neurology; the Bioinformatics Initiative of Osaka University Graduate School of Medicine; the Institute for Open and Transdisciplinary Research Initiatives; the Center for Infectious Disease Education and Research (CiDER); the Center for Advanced Modality and DDS (CAMaD), Osaka University; and RIKEN Advanced General Intelligence for Science Program (TRIP-AGIS). We would like to thank all the participants involved in this study. We sincerely thank Dr. Michiaki Kubo and the members of the RIKEN Center for Integrative Medical Sciences for their support of this study. This research was supported by the KAKENHI Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) (grant nos. 23K14451 [to K.S.] and 22H00476 [to Y.O.]); the Japan Agency for Medical Research and Development (AMED) (grant nos. JP24km0405217 , JP24ek0109594 , JP24ek0410113 , JP24kk0305022 , JP243fa627002 , JP243fa627010 , JP243fa627011 , JP24zf0127008 , JP24tm0524002 , JP24wm0625504 , and JP24gm1810011 [to Y.O.]); JST Moonshot R&D (grant nos. JPMJMS2021 and JPMJMS2024 [to Y.O.]); the Takeda Science Foundation; the Ono Pharmaceutical Foundation for Oncology , Immunology, and Neurology; the Bioinformatics Initiative of Osaka University Graduate School of Medicine; the Institute for Open and Transdisciplinary Research Initiatives; the Center for Infectious Disease Education and Research (CiDER); and the Center for Advanced Modality and DDS (CAMaD), Osaka University .; https://hdl.handle.net/10138/594302; 86000470520; 001447496800001 |
| Availability: |
https://hdl.handle.net/10138/594302 |
| Rights: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.541F164D |
| Database: |
BASE |