Clonal Hematopoiesis: A Global Health Perspective on CH Prevalence in Uganda Versus the United States

Clonal hematopoiesis (CH) is an age-related phenomenon in which hematopoietic stem cells (HSCs) acquire somatic mutations that confer a survival advantage and thereby clonal dominance. The mutations implicated in CH are in genes that are known drivers of leukemia. CH is considered a hematologic malignancy precursor state: carriers of a CH mutation have a 13-fold increased risk of hematologic malignancy. Interestingly, CH also increases the risk of a number of non-malignant disease states and all-cause mortality.

Recent preclinical and clinical studies make clear that CH prevalence can vary due to environmental factors and inflammatory stimuli. Further, the prevalence of CH varies widely between individuals but cannot be explained by differences in the rate of mutation acquisition alone. Our group has previously demonstrated in a mouse model that infection is a driver of CH. This relationship holds true in clinical studies as well: people living with HIV (PLWH) have an increased risk of CH as compared to age-matched controls without HIV.

The worldwide distribution of infection is unequal. Sub-Saharan Africa (SSA) shoulders a significant burden of infections with the highest prevalence of HIV, malaria, and tuberculosis. The impact of geography (endemic infection) on CH prevalence is unknown. We hypothesize that CH is more prevalent in areas of the world with increased burden of endemic infections. Comparison of matched populations in Uganda and the United States will illustrate the impact of infection burden on CH and will provide critical CH prevalence data in this Sub-Saharan population. Additionally, the specific CH mutations in SSA may be different from those previously described in other regions of the world due to genetic ancestry and environmental factors. Our work is uniquely designed to address this gap of knowledge.

To determine the impact of geography on CH, we designed a retrospective cohort study to compare CH in PLWH in Uganda with a frequency matched population in the United States. Study participants were selected from two prospective epidemiology studies: MACS/WIHS Combined Cohort Study (MWCCS, United States) and Ugandan AIDS Rural Treatment Outcomes (UARTO, from the AIDS and Cancer Specimen Resource (ACSR) biorepository). We selected participants who were self-reported African American or Black men and women ≥ 40 years of age with confirmed HIV infection and without documented malignancy. Clinical data was provided by MWCCS and the ACSR to include in our analysis. CH was detected via whole exome sequencing. A previously validated somatic mutation calling pipeline was utilized to identify known and novel CH mutations. Mutations with variant allele frequency > 1% were retained for further analysis. Sequencing analysis and sub-analyses are ongoing to determine the prevalence and specific genes mutated in our study population.

Of the 750 participants in the UARTO study, 193 were eligible for this study and 172 were included in our analysis. Of the 12,102 participants in MWCCS, 611 were eligible for this study and 178 were included in our analysis. American study participants had a median age of 51 years (IQR: 46.00 -57.00). Ugandan study participants had a median age of 50.1 years (IQR: 46.33 - 54.35). Most of the American study participants (n = 120, 67%) were on antiretroviral therapy at time of sample collection, with median viral load of 478.50 copies/mL (IQR: 35 - 12,383) and CD4 count of 459.50 cells/m³ (IQR: 264.50 - 717.80). All of the Ugandan study participants were on antiretroviral therapy at time of sample collection, with median viral load of 20 copies/mL (IQR: 20 - 20) and CD4 count of 421 cells/m³ (IQR: 308.00 - 547.00). Nearly half (n = 77, 45%) of the Ugandan study participants have documented Kaposi's sarcoma-associated herpesvirus infection. The most common self-reported infections for the American study participants were gonorrhea (n = 54, 30%), urethritis (n = 58, 33%), and trichomonas (n = 55, 31%).

This study is the first to characterize CH in SSA and provides necessary insight into whether geographical locations with differing burden of infectious disease exposure can impact CH.

No relevant conflicts of interest to declare.