Abstract / Summary
Clonal haematopoiesis (CH) arises from somatic mutations in haematopoietic stem cells that drive clonal expansion and increase haematological malignancy risk. Here we show that CH confers mutation- and dose-dependent risk of serious bacterial infection (SBI). Using a multi-parameter somatic variant calling and filtering approach, we identified 19,822 mutations across 43 CH genes in 40,560 of 590,537 individuals from three population cohorts (6.87%), validated in a combined analysis of 889,215 individuals. CH was associated with SBI development (HR = 1.22, P = 4.66 × 10⁻²⁹) and 28-day post-infection mortality (RR = 1.84, P = 0.0012), independent of malignancy and robust to adjustment for inflammatory comorbidities and ancestry. Recurrent mutations in SRSF2, DNMT3A, SF3B1, IDH2, and NRAS (n = 2143) conferred substantial absolute risks: 22–25% of individuals with expanded SRSF2 P95 clones developed SBI within 10 years. These associations were consistent across diverse populations and largely independent of bacterial strain. Fewings et al. show that clonal haematopoiesis confers subtype- and dose-dependent risk of serious bacterial infection, with splicing-factor mutations carrying the greatest hazard, validated across five biobank cohorts totalling 889,215 individuals.