Genetic markers, both in and outside the immune system, influence an individual’s response to the SARS-CoV-2 vaccine, and these effects are similar in patients with or without systemic autoimmune diseases (SADs), reports a study.
“This suggests that standard vaccination strategies remain appropriate for people with autoimmune conditions, and that genetics play a role in shaping individual vaccine responses,” the investigators said.
In this genome-wide association study (GWAS), the investigators identified genetic variants associated with postvaccination anti‒SARS-CoV-2 IgG antibody levels and determined whether these relationships differed between patients with SAD and healthy individuals.
Overall, 165 participants were included, including 138 with SADs and 27 healthy controls. All of them received nucleic acid‒based vaccines. [J Rheumatol 2026;53:456-462]
Between 1 and 12 months after vaccination, the investigators measured antibody levels targeting the spike protein receptor-binding domain (RBD) and nucleocapsid. Results of the GWAS were then included in a meta-analysis, with data from a previously published GWAS involving 1,076 healthy individuals.
A novel association was observed near RACGAP1 (rs706785; βmeta=−0.30; pmeta=3.85 × 10−8). A known association at HLA-DRB1 position 71 was also replicated (βmeta=−0.23; pmeta=1.94 × 10−11). Interactions between genotype and disease status were not significant.
“The integration of our findings with data from a prior GWAS significantly increased statistical power, enabling cross-study validation and the discovery of a novel locus associated with antibody levels,” the investigators said. [Nat Med 2023;29:147-157]
“This combined analysis not only reinforced the evidence for previously implicated genetic variants but also identified variants around RACGAP1 as a potential contributor to the variability in vaccine-induced immune responses,” they added.
Candidate genes
Several candidate genes regulated by credible-set variants around RACGAP1 have been identified, but direct evidence on their link to vaccine efficacy or antibody levels remains scarce.
“Among these, RACGAP1, a member of the Rho GTPase–activating protein family, is primarily known for critical roles in cytokinesis, cell migration, and invasion through its regulation of cytoskeletal dynamics and signalling pathways,” according to the investigators. [Proc Natl Acad Sci U S A 2005;102:13158-13163; Int J Clin Oncol 2024;29:333-434]
“Although RACGAP1 has been extensively studied in cancer biology, where its overexpression is associated with poor prognosis across various malignancies, its role in immune responses remains poorly understood,” they added.
Previous findings on the relationship between RACGAP1 expression in various cancer cells and immune cell infiltration point to a potential role in modulating immune cell dynamics and responsiveness. [Int J Mol Sci 2022;23:14102]
“In the context of vaccine-induced immunity, the observed association of RACGAP1 expression–reducing alleles with lower antibody titers suggests that these alleles may weaken immune cell activation or recruitment, potentially dampening vaccine efficacy,” the investigators said.
“Further functional studies and independent GWAS are needed to validate our findings and to clarify potential mechanisms and their implications for immune responses,” they added.