Association of infection frequency and incident clonal hematopoiesis of indeterminant potential

Clonal hematopoiesis of indeterminant potential (CHIP) is an age-related phenomenon associated with increased risk of hematologic malignancy. Preclinical studies have shown that infection is a driver of CHIP; clinical studies in people living with HIV suggest a relationship between chronic infection and CHIP, but the association between infection frequency and incident CHIP in the general population remains unknown. We leveraged the atherosclerosis risk in communities study to design a closed prospective cohort study. CHIP was determined based on whole-exome sequencing at 2 time points 20 years apart. Included were 3,367 individuals without cancer or CHIP at time 1 and without hematologic malignancy by time 2. The 3,367 study participants had an average age of 55.3 years at time 1; 59.1% were women, 40.9% were men; 24% were Black, and 76% were White. Documented infection was assessed from routinely collected hospital discharge summaries. Frequency was categorized as no documented infection, 1 infection, 2 infections, or ≥3 infections. Of the participants, 19.7% had incident CH, 6.9% had large CHIP, and 5.2% had large non-DNMT3A CHIP. Participants with ≥3 documented infections had an increased odds of incident CHIP (odds ratios OR 1.41, p = 0.03), especially large CHIP (OR 1.83, p = 0.008) and large non-DNMT3A CHIP (OR 1.81; p = 0.02). To our knowledge, this study is the first to demonstrate an association between infection and incident CHIP in a general population, highlighting a modifiable risk factor for CHIP. Further work is required to describe the mutation-specific impact underlying this observed relationship.