Rare germline JAK/STAT variants in a Korean cohort amplify innate immune responses to vaccination

Abstract

The JAK/STAT signaling pathway regulates cytokine-driven responses. Here we investigated the biological impact of germline single nucleotide variants in JAK kinases and STAT transcription factors in vaccine response. First, we applied a data-mining strategy to RNA-seq datasets from a Korean cohort to uncover JAK/STAT germline variants and analyzed their corresponding interferon transcriptomic responses. Ultra-rare variants associated with heightened interferon transcriptomic responses were identified. AlphaFold 3 predicted conformational alterations in these JAK and STAT variants, focusing on protein-protein interactions and receptor-complex assembly. Co-occurring variants in TYK2 and other interferon signaling regulators that could influence the impact of the JAK and STAT variants were explored. We found that data mining can reveal candidate germline variants with potential roles in innate immunity and assessed how analyzing vaccine-induced gene expression changes can serve as an in vivo method to functionally assess the biological significance of missense mutations in key immune signaling pathways. © 2025 The Author(s)