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Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

ABSTRACT: Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. In this study, we trained machine learning models for 12 of the most recurrent CH genes to identify their driver mutations. These models outperform expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals. Significance: We developed and validated gene-specific machine learning models to identify CH driver mutations, showing their advantage with respect to expert-curated rules. These models can support the identification and clinical interpretation of CH mutations in newly sequenced individuals. See related commentary by Arends and Jaiswal, p. 1581.

SUBMITTER: Demajo S

PROVIDER: S-EPMC11372364 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

Demajo Santiago S Ramis-Zaldivar Joan E JE Muiños Ferran F Grau Miguel L ML Andrianova Maria M López-Bigas Núria N González-Pérez Abel A

Cancer discovery 20240901 9

Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. In this study, we trained machine learning models for 12 of th ...[more]

PMID: 38722595

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Project description:BackgroundObesity is accompanied by dysregulated inflammation, which can contribute to vasculometabolic complications including metabolic syndrome and atherosclerosis. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular diseases. We aimed to determine how CHIP is related to immune cell function, systemic inflammation, and vasculometabolic complications in obese individuals.Methods and resultsTwo hundred ninety-seven individuals with overweight and obesity, between the ages of 54 and 81 years, were recruited in a cross-sectional study. Clonal hematopoiesis driver mutations (CHDMs) were identified with an ultrasensitive targeted assay. Assessment of carotid artery atherosclerosis was performed with ultrasound. Detailed immunological parameters, including cytokine production capacity of peripheral blood mononuclear cells, and targeted plasma proteomics analysis, were studied. Adipose tissue inflammation was determined in subcutaneous fat biopsies. Individuals with CHIP had higher concentrations of circulating IL (interleukin)-6. Total number of leukocytes and neutrophils were higher in individuals with CHIP. In contrast, ex vivo cytokine production capacity of peripheral blood mononuclear cells was significantly lower in individuals with CHIP. Sex-stratified analysis showed that men with CHDMs had significantly higher leukocyte and neutrophil counts, and ex vivo cytokine production capacity was lower in women with CHDMs. Surprisingly, the presence of atherosclerotic plaques was significantly lower in individuals with CHDMs. There was no relation between CHIP and metabolic syndrome.ConclusionsIn individuals with overweight or obesity, CHDMs are not associated with vasculometabolic complications, but rather with a lower presence of carotid plaques. CHDMs associate with increased circulating inflammatory markers and leukocyte numbers, but a lower peripheral blood mononuclear cell cytokine production capacity.

Dataset Information

Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

Publications

Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

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