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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 (ARIC) study to design a closed prospective cohort study. CHIP was determined based on whole-exome sequencing at two 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 female, 40.9% were male; 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 (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). 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. Teaser Abstract: Clonal Hematopoiesis of Indeterminant Potential (CHIP) is a malignancy precursor state that has been shown in preclinical models to be accelerated by infection. We leveraged an ongoing epidemiology study to determine the relationship between infection frequency and incident CHIP. CHIP was determined via whole-exome sequencing at two time points. Documented infection was assessed from routinely collected hospital discharge summaries. Participants with ≥ 3 documented infections had an increased odds of incident CHIP, especially large non-DNMT3A CHIP. 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.