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

IF 11.1 Q1 CELL BIOLOGY

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-03-04 DOI:10.1016/j.xgen.2025.100783

Kyuto Sonehara, Yoshifumi Uwamino, Ryunosuke Saiki, Masaru Takeshita, Shinichi Namba, Shunsuke Uno, Tomoko Nakanishi, Tomoyasu Nishimura, Tatsuhiko Naito, Go Sato, Masahiro Kanai, Aoxing Liu, Sho Uchida, Toshinobu Kurafuji, Akiko Tanabe, Tomoko Arai, Akemi Ohno, Ayako Shibata, Shiho Tanaka, Masatoshi Wakui, Shoko Kashimura, Chiharu Tomi, Akemi Hara, Shiori Yoshikawa, Keiko Gotanda, Kana Misawa, Hiromu Tanaka, Shuhei Azekawa, Qingbo S Wang, Ryuya Edahiro, Yuya Shirai, Kenichi Yamamoto, Genta Nagao, Takuo Suzuki, Masato Kiyoshi, Akiko Ishii-Watabe, Shinichi Higashiue, Shuzo Kobayashi, Hiroki Yamaguchi, Yasushi Okazaki, Naoyuki Matsumoto, Akihide Masumoto, Hidenobu Koga, Akinori Kanai, Yoshiya Oda, Yutaka Suzuki, Koichi Matsuda, Yuko Kitagawa, Ryuji Koike, Akinori Kimura, Atsushi Kumanogoh, Akihiko Yoshimura, Seiya Imoto, Satoru Miyano, Takanori Kanai, Koichi Fukunaga, Naoki Hasegawa, Mitsuru Murata, Hiromichi Matsushita, Seishi Ogawa, Yukinori Okada, Ho Namkoong

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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.

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来源期刊

Cell genomics

CiteScore

7.10

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0.00%

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